ClinVar

Description

The c.477A>G variant in MYOC is a synonymous variant (p.Leu159=). The highest minor allele frequency of this variant was in the African/African-American population of gnomAD (v2.1.1) = 0.07458, which met the >= 0.01 threshold set for BA1 (1,860 alleles out of 24,938, meeting the threshold of >= 5 of at least 2,000 observed alleles). The CADD score (v1.6) = 6.353, 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. However, BP7 was not met as this variant had a GERP score = 4.49 (threshold <0), indicating conservation at this site. As BA1 was met, PP1 did not apply and segregations were not counted. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant was classified as benign (BA1 is a stand-alone criterion for a benign level of pathogenicity) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BA1, BP4.