rs61730977

Positions:

• chr1-171652135-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4 BA1

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA1244271/MONDO:0020367/019

• Frequency:
  • Genomes: 𝑓 0.021 (120 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (112 hom.)
• Consequence: MYOC NM_000261.2 synonymous
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: 0.776

Genes affected

MYOC (HGNC:7610): (myocilin) MYOC encodes the protein myocilin, which is believed to have a role in cytoskeletal function. MYOC is expressed in many occular tissues, including the trabecular meshwork, and was revealed to be the trabecular meshwork glucocorticoid-inducible response protein (TIGR). The trabecular meshwork is a specialized eye tissue essential in regulating intraocular pressure, and mutations in MYOC have been identified as the cause of hereditary juvenile-onset open-angle glaucoma. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOC	NM_000261.2	c.477A>G	p.Leu159=	synonymous_variant	1/3	ENST00000037502.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOC	ENST00000037502.11	c.477A>G	p.Leu159=	synonymous_variant	1/3	1	NM_000261.2	P1
MYOC	ENST00000638471.1	c.130+347A>G		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0210 AC: 3202 AN: 152138 Hom.: 120 Cov.: 32

Gnomad AFR AF: 0.0724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00929

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.00570 AC: 1434 AN: 251448 Hom.: 55 AF XY: 0.00421 AC XY: 572 AN XY: 135900

Gnomad AFR exome AF: 0.0726

Gnomad AMR exome AF: 0.00416

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000536

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00227 AC: 3314 AN: 1461892 Hom.: 112 Cov.: 32 AF XY: 0.00194 AC XY: 1408 AN XY: 727248

Gnomad4 AFR exome AF: 0.0741

Gnomad4 AMR exome AF: 0.00443

Gnomad4 ASJ exome AF: 0.000918

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000230

Gnomad4 OTH exome AF: 0.00512

GnomAD4 genome AF: 0.0211 AC: 3213 AN: 152256 Hom.: 120 Cov.: 32 AF XY: 0.0202 AC XY: 1505 AN XY: 74442

Gnomad4 AFR AF: 0.0724

Gnomad4 AMR AF: 0.00928

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00937 Hom.: 32

Bravo AF: 0.0241

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Glaucoma 1, open angle, A Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Glaucoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Glaucoma of childhood Benign:1

Benign, reviewed by expert panel

curation

ClinGen Glaucoma Variant Curation Expert Panel

Feb 07, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.8
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61730977; hg19: chr1-171621275;