1-171636252-C-T

Position:

chr1-171636252-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP7BA1BP4

This summary comes from the ClinGen Evidence Repository: The c.1188G>A variant in MYOC is a synonymous variant (p.Glu396=). The highest minor allele frequency of this variant was in the African/African American population of gnomAD (v2.1.1) = 0.02893, which met the ≥ 0.01 threshold set for BA1 (722 alleles out of 24,958, 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) = 0.360 which met the ≤ 10 threshold for BP4, and the GERP score = -4.66 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Although probands with POAG 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 primary 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/CA1244067/MONDO:0007665/019

Frequency

Genomes: 𝑓 0.0079 ( 15 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 11 hom. )

Consequence

MYOC
NM_000261.2 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:5

Conservation

PhyloP100: -0.874

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 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.1188G>A	p.Glu396=	synonymous_variant	3/3	ENST00000037502.11	NP_000252.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MYOC	ENST00000037502.11 linkuse as main transcript	c.1188G>A	p.Glu396=	synonymous_variant	3/3	1	NM_000261.2	ENSP00000037502	P1
MYOCOS	ENST00000637303.1 linkuse as main transcript	c.235-2378C>T		intron_variant		5		ENSP00000490048	A2
MYOC	ENST00000638471.1 linkuse as main transcript	c.*526G>A		3_prime_UTR_variant, NMD_transcript_variant	4/4	5		ENSP00000491206

Frequencies

GnomAD3 genomes

AF:

0.00786

AC:

1196

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0275

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00766

GnomAD3 exomes

AF:

0.00208

AC:

523

AN:

251424

Hom.:

AF XY:

0.00145

AC XY:

197

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.0296

Gnomad AMR exome

AF:

0.000896

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000749

AC:

1095

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000660

AC XY:

480

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0274

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.00167

GnomAD4 genome

AF:

0.00793

AC:

1207

AN:

152222

Hom.:

Cov.:

AF XY:

0.00730

AC XY:

543

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0277

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.00432

Hom.:

Bravo

AF:

0.00892

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	- -

Glaucoma 1, open angle, A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 12, 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 1, open angle, E

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Glaucoma Variant Curation Expert Panel

May 09, 2022

The c.1188G>A variant in MYOC is a synonymous variant (p.Glu396=). The highest minor allele frequency of this variant was in the African/African American population of gnomAD (v2.1.1) = 0.02893, which met the >= 0.01 threshold set for BA1 (722 alleles out of 24,958, 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) = 0.360 which met the <= 10 threshold for BP4, and the GERP score = -4.66 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Although probands with POAG 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 primary 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

-0.78

CADD

Benign

0.17

DANN

Benign

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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