Variant: NM_005629.4(SLC6A8):c.1221C>T (p.Phe407=)

CA10549449

795105 (ClinVar)

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: debab09a-c8ee-458c-be59-38383efb1e59

Approved on: 2025-04-11

Published on: 2025-04-11

HGVS expressions

NM_005629.4:c.1221C>T
NM_005629.4(SLC6A8):c.1221C>T (p.Phe407=)
NC_000023.11:g.153693984C>T
CM000685.2:g.153693984C>T
NC_000023.10:g.152959439C>T
CM000685.1:g.152959439C>T
NC_000023.9:g.152612633C>T
NG_012016.1:g.10688C>T
NG_012016.2:g.10688C>T
ENST00000253122.10:c.1221C>T
ENST00000253122.9:c.1221C>T
ENST00000413787.1:c.258-220C>T
ENST00000430077.6:c.876C>T
ENST00000442457.1:c.275C>T
ENST00000457723.1:c.205C>T
ENST00000485324.1:n.1254C>T
NM_001142805.1:c.1191C>T
NM_001142806.1:c.876C>T
NM_005629.3:c.1221C>T
NM_001142805.2:c.1191C>T

Likely Benign

• Met criteria codes: BS2 BP7 BP4

• Not Met criteria codes: BS1 PM2

Expert Panel

Cerebral Creatine Deficiency Syndromes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC6A8 Version 1.1.0

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_005629.4:c.1221C>T variant in SLC6A8 is a synonymous variant (p.Phe407=) with no predicted impact on splicing (BP4, BP7). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0. the highest population minor allele frequency (MAF) is 0.0001849 (6/32453 alleles; 1 hemizygote) in the East Asian population. This is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. There is a total of 2 hemizygotes in gnomAD v4.1.0.; one in the East Asian population and one in the remaining population (BS2). There is a ClinVar entry for this variant (Variation ID: 795105). In summary, this variant meets criteria to be classified as likely benign for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2, BP4, BP7. (Classification approved by the ClinGen CCDS VCEP on April 11, 2025)

Met criteria codes

• BS2: There is a total of 2 hemizygotes in gnomAD v4.1.0.; one in the East Asian population and one in the remaining population (BS2).
• BP7: The NM_005629.4:c.1221C>T variant in SLC6A8 is a synonymous variant (p.Phe407=) with no predicted impact on splicing. Although the variant is highly conserved (PhyloP score 3.11), recent guidance indicates that "conservation has limited predictive power to detect non-splice disrupting variants" (BP7).
• BP4: The in silico predictor, SpliceAI, predicts that the variant has no impact on splicing (all scores <0.1) (BP4).

Not Met criteria codes

• BS1: In gnomAD v4.1.0. the highest population minor allele frequency (MAF) is 0.0001849 (6/32453 alleles; 1 hemizygote) in the East Asian population. This is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met.
• PM2: In gnomAD v4.1.0. the highest population minor allele frequency (MAF) is 0.0001849 (6/32453 alleles; 1 hemizygote) in the East Asian population. This is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met.