chr1-171652385-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.227G>A variant in MYOC is a missense variant predicted to cause substitution of Arginine by Lysine at amino acid 76 (p.Arg76Lys). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.3468, which met the ≥ 0.01 threshold set for BA1 (10,613 alleles out of 30,602, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.203, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Arg76Lys protein had similar solubility and secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. 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, BS3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA200294/MONDO:0020367/019

Frequency

Genomes: 𝑓 0.11 ( 1253 hom., cov: 32)

Exomes 𝑓: 0.14 ( 17310 hom. )

Consequence

MYOC
NM_000261.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:8

Conservation

PhyloP100: 2.86

Variant links:

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]

MYOC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOC	NM_000261.2 link	c.227G>A	p.Arg76Lys	missense_variant	Exon 1 of 3	ENST00000037502.11	NP_000252.1	Q99972A0A0S2Z421

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOC	ENST00000037502.11 link	c.227G>A	p.Arg76Lys	missense_variant	Exon 1 of 3	1	NM_000261.2	ENSP00000037502.5		Q99972
MYOC	ENST00000638471.1 link	n.130+97G>A		intron_variant	Intron 1 of 3	5		ENSP00000491206.1		A0A1W2PP09

Frequencies

GnomAD3 genomes

AF:

0.108

AC:

16415

AN:

152108

Hom.:

1252

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0259

Gnomad AMI

AF:

0.130

Gnomad AMR

AF:

0.102

Gnomad ASJ

AF:

0.138

Gnomad EAS

AF:

0.0758

Gnomad SAS

AF:

0.345

Gnomad FIN

AF:

0.169

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.133

Gnomad OTH

AF:

0.112

GnomAD3 exomes

AF:

0.147

AC:

37010

AN:

251002

Hom.:

3720

AF XY:

0.160

AC XY:

21758

AN XY:

135594

show subpopulations

Gnomad AFR exome

AF:

0.0218

Gnomad AMR exome

AF:

0.0997

Gnomad ASJ exome

AF:

0.127

Gnomad EAS exome

AF:

0.0817

Gnomad SAS exome

AF:

0.347

Gnomad FIN exome

AF:

0.164

Gnomad NFE exome

AF:

0.136

Gnomad OTH exome

AF:

0.143

GnomAD4 exome

AF:

0.141

AC:

206715

AN:

1461048

Hom.:

17310

Cov.:

AF XY:

0.148

AC XY:

107803

AN XY:

726668

show subpopulations

Gnomad4 AFR exome

AF:

0.0237

Gnomad4 AMR exome

AF:

0.102

Gnomad4 ASJ exome

AF:

0.132

Gnomad4 EAS exome

AF:

0.0568

Gnomad4 SAS exome

AF:

0.341

Gnomad4 FIN exome

AF:

0.162

Gnomad4 NFE exome

AF:

0.134

Gnomad4 OTH exome

AF:

0.137

GnomAD4 genome

AF:

0.108

AC:

16424

AN:

152226

Hom.:

1253

Cov.:

AF XY:

0.112

AC XY:

8337

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0258

Gnomad4 AMR

AF:

0.102

Gnomad4 ASJ

AF:

0.138

Gnomad4 EAS

AF:

0.0762

Gnomad4 SAS

AF:

0.346

Gnomad4 FIN

AF:

0.169

Gnomad4 NFE

AF:

0.133

Gnomad4 OTH

AF:

0.112

Alfa

AF:

0.120

Hom.:

760

Bravo

AF:

0.0936

TwinsUK

AF:

0.131

AC:

484

ALSPAC

AF:

0.125

AC:

482

ESP6500AA

AF:

0.0277

AC:

122

ESP6500EA

AF:

0.134

AC:

1155

ExAC

AF:

0.150

AC:

18209

Asia WGS

AF:

0.199

AC:

693

AN:

3478

EpiCase

AF:

0.137

EpiControl

AF:

0.139

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 18449353, 17361544, 28792703, 22449891, 15025728, 27884173, 21168818, 23029558, 14688426, 23517641, 16466712) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:2

Jun 10, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glaucoma 1, open angle, A

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Glaucoma

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Glaucoma of childhood

Benign:1

Mar 05, 2022

ClinGen Glaucoma Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.227G>A variant in MYOC is a missense variant predicted to cause substitution of Arginine by Lysine at amino acid 76 (p.Arg76Lys). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.3468, which met the >= 0.01 threshold set for BA1 (10,613 alleles out of 30,602, meeting the threshold of >= 5 of at least 2,000 observed alleles). The REVEL score = 0.203, which was neither above nor below the thresholds for PP3 (>= 0.7) or BP4 (<= 0.15), predicting a damaging or benign impact on MYOC function. Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Arg76Lys protein had similar solubility and secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. 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, BS3_Moderate. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.38

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0041

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.8

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.87

REVEL

Benign

0.20

Sift

Benign

0.049

Sift4G

Benign

0.077

Polyphen

0.018

Vest4

0.064

MPC

0.19

ClinPred

0.064

GERP RS

3.4

Varity_R

0.13

gMVP

0.47

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over