NM_000261.2:c.1239C>T

CA1244059

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: ca420800-6892-425d-96d9-42abca9e461b

Approved on: 2022-11-10

Published on: 2022-11-10

HGVS expressions

NM_000261.2:c.1239C>T
NC_000001.11:g.171636201G>A
CM000663.2:g.171636201G>A
NC_000001.10:g.171605341G>A
CM000663.1:g.171605341G>A
NC_000001.9:g.169871964G>A
NG_008859.1:g.21433C>T
ENST00000037502.11:c.1239C>T
ENST00000637303.1:c.235-2429G>A
ENST00000638471.1:c.*577C>T
ENST00000037502.10:c.1239C>T
ENST00000614688.1:c.*203C>T
NM_000261.1:c.1239C>T

Likely Benign

• Met criteria codes: BP4 BP7

• Not Met criteria codes: PM6 PM2 PM5 PM4 PS2 PS1 PS3 PS4 BA1 PP1 PP3 BS3 BS1

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Evidence submitted by expert panel

Glaucoma VCEP

The c.1239C>T variant in MYOC is a synonymous variant (p.Leu413=). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0001633 (5 alleles out of 30,616), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). This variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), with a CADD score (v1.6) = 0.006 which met the ≤ 10 threshold for BP4, and the GERP score = -10.3 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Although a proband with primary open angle glaucoma had been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -2 and to be classified as likely benign (likely benign classification range -2 to -6) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BP4, BP7

Met criteria codes

• BP4: The CADD score (v1.6) = 0.006, which met the ≤ 10 threshold for BP4 and this variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), suggesting that the variant does not impact MYOC function.
• BP7: This synonymous/non-coding variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2) and had a GERP score = -10.3 (threshold <0), indicating a lack of conservation at this site.

Not Met criteria codes

• PM6: This variant has not been identified de novo.
• PM2: The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0001633 (5 alleles out of 30,616), which did not meet the ≤ 0.0001 threshold set for PM2_Supporting.
• PM5: This is not a missense variant.
• PM4: This variant does not cause a protein length change.
• PS2: This variant has not been identified de novo.
• PS1: This variant does not involve an amino acid change.
• PS3: No functional evidence has been found for this variant.
• PS4: Although a proband with POAG had been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply.
• BA1: This variant did not meet the ≥ 0.01 minor allele frequency threshold in gnomAD (v2.1.1).
• PP1: No segregations have been reported for this variant.
• PP3: This is not a missense variant.
• BS3: No functional evidence has been found for this variant.
• BS1: The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0001633 (5 alleles out of 30,616), which did not meet the ≥ 0.001 threshold set for BS1.