1-171638703-G-C

Position:

chr1-171638703-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1BP4

This summary comes from the ClinGen Evidence Repository: The c.624C>G variant in MYOC is a missense variant predicted to cause substitution of Aspartic acid by Glutamic acid at amino acid 208 (p.Asp208Glu). The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.007468, which met the ≥ 0.001 threshold set for BS1 (149 alleles out of 19,952, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.126, which met the ≤ 0.15 threshold for BP4, suggesting that the variant does not impact MYOC function. The studies reporting functional evidence (PMIDs: 27092720, 14688426) demonstrated that the Asp208Glu protein had similar secretion levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (< 0.48) for BS3_Supporting to be applied. As BS1 was met, PP1 did not apply and segregations were not counted. Although probands with primary open angle glaucoma have 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 -5 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): BS1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA1244210/MONDO:0007665/019

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00037 ( 6 hom. )

Consequence

MYOC
NM_000261.2 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel B:3

Conservation

PhyloP100: 0.342

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:

MYOCOS (HGNC:53429): (myocilin opposite strand)

MYOCOS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

BS1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOC	NM_000261.2 linkuse as main transcript	c.624C>G	p.Asp208Glu	missense_variant	2/3	ENST00000037502.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MYOC	ENST00000037502.11 linkuse as main transcript	c.624C>G	p.Asp208Glu	missense_variant	2/3	1	NM_000261.2	P1
MYOCOS	ENST00000637303.1 linkuse as main transcript	c.308G>C	p.Cys103Ser	missense_variant	4/4	5		A2
MYOC	ENST00000638471.1 linkuse as main transcript	c.154C>G	p.His52Asp	missense_variant, NMD_transcript_variant	3/4	5

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00539

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000764

AC:

192

AN:

251444

Hom.:

AF XY:

0.000633

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00756

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00157

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000372

AC:

544

AN:

1461826

Hom.:

Cov.:

AF XY:

0.000381

AC XY:

277

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00814

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00161

Gnomad4 NFE exome

AF:

0.000102

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000315

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00541

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000848

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000463

Hom.:

Bravo

AF:

0.000291

ExAC

AF:

0.000684

AC:

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glaucoma 1, open angle, A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Glaucoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Glaucoma 1, open angle, E

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Glaucoma Variant Curation Expert Panel

Feb 20, 2022

The c.624C>G variant in MYOC is a missense variant predicted to cause substitution of Aspartic acid by Glutamic acid at amino acid 208 (p.Asp208Glu). The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.007468, which met the >= 0.001 threshold set for BS1 (149 alleles out of 19,952, meeting the threshold of >= 5 of at least 2,000 observed alleles). The REVEL score = 0.126, which met the <= 0.15 threshold for BP4, suggesting that the variant does not impact MYOC function. The studies reporting functional evidence (PMIDs: 27092720, 14688426) demonstrated that the Asp208Glu protein had similar secretion levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (< 0.48) for BS3_Supporting to be applied. As BS1 was met, PP1 did not apply and segregations were not counted. Although probands with primary open angle glaucoma have 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 -5 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): BS1, BP4. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.73

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.036

M_CAP

Benign

0.0071

MetaRNN

Benign

0.0045

MutationTaster

Benign

1.0

ClinPred

0.0078

GERP RS

2.5

gMVP

0.0056

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