1-171652573-A-C

Position:

chr1-171652573-A-C

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.39T>G variant in MYOC is a synonymous variant (p.Pro13=). The highest minor allele frequency of this variant was in the African/African-American population of gnomAD (v2.1.1) = 0.07477, which met the ≥ 0.01 threshold set for BA1 (1,865 alleles out of 24,942, 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) = 0.647 which met the ≤ 10 threshold for BP4, and the GERP score = -1.38 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant did 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/CA1244342/MONDO:0020367/019

Frequency

Genomes: 𝑓 0.021 ( 119 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 112 hom. )

Consequence

MYOC
NM_000261.2 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:6

Conservation

PhyloP100: -0.0670

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:

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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 link	c.39T>G	p.Pro13Pro	synonymous_variant	1/3	ENST00000037502.11	NP_000252.1	Q99972A0A0S2Z421

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOC	ENST00000037502.11 link	c.39T>G	p.Pro13Pro	synonymous_variant	1/3	1	NM_000261.2	ENSP00000037502.5		Q99972
MYOC	ENST00000638471.1 link	n.39T>G		non_coding_transcript_exon_variant	1/4	5		ENSP00000491206.1		A0A1W2PP09

Frequencies

GnomAD3 genomes

AF:

0.0211

AC:

3208

AN:

152190

Hom.:

119

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00922

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:

0.0144

GnomAD3 exomes

AF:

0.00575

AC:

1431

AN:

249014

Hom.:

AF XY:

0.00423

AC XY:

570

AN XY:

134830

show subpopulations

Gnomad AFR exome

AF:

0.0725

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:

0.000539

Gnomad OTH exome

AF:

0.00556

GnomAD4 exome

AF:

0.00227

AC:

3315

AN:

1461876

Hom.:

112

Cov.:

AF XY:

0.00194

AC XY:

1408

AN XY:

727238

show subpopulations

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:

3219

AN:

152308

Hom.:

119

Cov.:

AF XY:

0.0203

AC XY:

1510

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0726

Gnomad4 AMR

AF:

0.00921

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:

0.0107

Hom.:

Bravo

AF:

0.0241

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

LINK: link

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2018	- -

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

Glaucoma of childhood

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Glaucoma Variant Curation Expert Panel

Feb 07, 2022

The c.39T>G variant in MYOC is a synonymous variant (p.Pro13=). The highest minor allele frequency of this variant was in the African/African-American population of gnomAD (v2.1.1) = 0.07477, which met the >= 0.01 threshold set for BA1 (1,865 alleles out of 24,942, 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) = 0.647 which met the <= 10 threshold for BP4, and the GERP score = -1.38 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant did 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

-0.91

CADD

Benign

3.3

DANN

Benign

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