1-171636399-A-G

Variant names:

• chr1-171636399-A-G
• rs61730974
• NM_000261.2:c.1041T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BA1 BP7

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
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: -0.922
• Publications: 37 publications found

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]

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

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
MYOC	NM_000261.2	c.1041T>C	p.Tyr347Tyr	synonymous_variant	Exon 3 of 3	ENST00000037502.11	NP_000252.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOC	ENST00000037502.11	c.1041T>C	p.Tyr347Tyr	synonymous_variant	Exon 3 of 3	1	NM_000261.2	ENSP00000037502.5
MYOC	ENST00000638471.1	n.*379T>C		non_coding_transcript_exon_variant	Exon 4 of 4	5		ENSP00000491206.1
MYOC	ENST00000638471.1	n.*379T>C		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000491206.1
MYOCOS	ENST00000637303.1	c.235-2231A>G		intron_variant	Intron 3 of 3	5		ENSP00000490048.1

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3128 AN: 152072 Hom.: 56 Cov.: 32

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

GnomAD2 exomes AF: 0.0226 AC: 5679 AN: 251388 AF XY: 0.0228

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 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.: 31 AF XY: 0.0264 AC XY: 19212 AN XY: 727246

African (AFR) AF: 0.00424 AC: 142 AN: 33480

American (AMR) AF: 0.0195 AC: 874 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0815 AC: 2130 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0165 AC: 1423 AN: 86258

European-Finnish (FIN) AF: 0.00917 AC: 490 AN: 53420

Middle Eastern (MID) AF: 0.0550 AC: 317 AN: 5768

European-Non Finnish (NFE) AF: 0.0281 AC: 31219 AN: 1112006

Other (OTH) AF: 0.0299 AC: 1807 AN: 60396

GnomAD4 genome AF: 0.0205 AC: 3127 AN: 152190 Hom.: 56 Cov.: 32 AF XY: 0.0198 AC XY: 1472 AN XY: 74406

African (AFR) AF: 0.00470 AC: 195 AN: 41530

American (AMR) AF: 0.0258 AC: 395 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0703 AC: 244 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0166 AC: 80 AN: 4818

European-Finnish (FIN) AF: 0.00924 AC: 98 AN: 10604

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0299 AC: 2031 AN: 67988

Other (OTH) AF: 0.0304 AC: 64 AN: 2106

Alfa AF: 0.0264 Hom.: 142

Bravo AF: 0.0207

Asia WGS AF: 0.00577 AC: 21 AN: 3478

EpiCase AF: 0.0333

EpiControl AF: 0.0300

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Feb 26, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 20, 2022

ClinGen Glaucoma Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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
PhyloP100		-0.92
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61730974; hg19: chr1-171605539;