1-171636399-A-G

Position:

chr1-171636399-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4BA1BP7

This summary comes from the ClinGen Evidence Repository: The c.1041T>C variant in MYOC is a synonymous variant (p.Tyr347=). The highest minor allele frequency of this variant was in the Ashkenazi Jewish population of gnomAD (v2.1.1) = 0.08597, which met the ≥ 0.01 threshold set for BA1 (891 alleles out of 10,364, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). This variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), with a CADD score (v1.6) = 0.087 which met the ≤ 10 threshold for BP4, and the GERP score = -6 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant does not impact MYOC 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, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA1244091/MONDO:0020367/019

Frequency

Genomes: 𝑓 0.021 ( 56 hom., cov: 32)

Exomes 𝑓: 0.026 ( 655 hom. )

Consequence

MYOC
NM_000261.2 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:6

Conservation

PhyloP100: -0.922

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

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

BP7

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/exons	MANE	Protein	UniProt
MYOC	NM_000261.2 linkuse as main transcript	c.1041T>C	p.Tyr347Tyr	synonymous_variant	3/3	ENST00000037502.11	NP_000252.1	Q99972A0A0S2Z421

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYOC	ENST00000037502.11 linkuse as main transcript	c.1041T>C	p.Tyr347Tyr	synonymous_variant	3/3	1	NM_000261.2	ENSP00000037502.5	Q99972
MYOCOS	ENST00000637303.1 linkuse as main transcript	c.235-2231A>G		intron_variant		5		ENSP00000490048.1	A0A1B0GUC4
MYOC	ENST00000638471.1 linkuse as main transcript	n.*379T>C		non_coding_transcript_exon_variant	4/4	5		ENSP00000491206.1	A0A1W2PP09
MYOC	ENST00000638471.1 linkuse as main transcript	n.*379T>C		3_prime_UTR_variant	4/4	5		ENSP00000491206.1	A0A1W2PP09

Frequencies

GnomAD3 genomes

AF:

0.0206

AC:

3128

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00469

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0259

Gnomad ASJ

AF:

0.0703

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0166

Gnomad FIN

AF:

0.00924

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0299

Gnomad OTH

AF:

0.0302

GnomAD3 exomes

AF:

0.0226

AC:

5679

AN:

251388

Hom.:

109

AF XY:

0.0228

AC XY:

3102

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.00363

Gnomad AMR exome

AF:

0.0188

Gnomad ASJ exome

AF:

0.0870

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0158

Gnomad FIN exome

AF:

0.00892

Gnomad NFE exome

AF:

0.0284

Gnomad OTH exome

AF:

0.0300

GnomAD4 exome

AF:

0.0263

AC:

38404

AN:

1461886

Hom.:

655

Cov.:

AF XY:

0.0264

AC XY:

19212

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00424

Gnomad4 AMR exome

AF:

0.0195

Gnomad4 ASJ exome

AF:

0.0815

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0165

Gnomad4 FIN exome

AF:

0.00917

Gnomad4 NFE exome

AF:

0.0281

Gnomad4 OTH exome

AF:

0.0299

GnomAD4 genome

AF:

0.0205

AC:

3127

AN:

152190

Hom.:

Cov.:

AF XY:

0.0198

AC XY:

1472

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.00470

Gnomad4 AMR

AF:

0.0258

Gnomad4 ASJ

AF:

0.0703

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0166

Gnomad4 FIN

AF:

0.00924

Gnomad4 NFE

AF:

0.0299

Gnomad4 OTH

AF:

0.0304

Alfa

AF:

0.0274

Hom.:

Bravo

AF:

0.0207

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.0333

EpiControl

AF:

0.0300

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 26, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Glaucoma of childhood

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Glaucoma Variant Curation Expert Panel

Feb 20, 2022

The c.1041T>C variant in MYOC is a synonymous variant (p.Tyr347=). The highest minor allele frequency of this variant was in the Ashkenazi Jewish population of gnomAD (v2.1.1) = 0.08597, which met the >= 0.01 threshold set for BA1 (891 alleles out of 10,364, meeting the threshold of >= 5 of at least 2,000 observed alleles). This variant was not predicted to affect splicing, as assessed with SpliceAI (<= 0.2), with a CADD score (v1.6) = 0.087 which met the <= 10 threshold for BP4, and the GERP score = -6 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant does not impact MYOC 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, BP4, BP7. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.015

DANN

Benign

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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