1-171636244-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1196G>A variant in MYOC is a missense variant predicted to cause substitution of Glycine by Aspartate at amino acid 399 (p.Gly399Asp). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.953, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with juvenile open angle glaucoma had been reported (PMID:17562996), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 2 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA343724341/MONDO:0020367/019

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MYOC
NM_000261.2 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:1

Conservation

PhyloP100: 7.80

Publications

1 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

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

PP3

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000261.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOC	NM_000261.2	MANE Select	c.1196G>A	p.Gly399Asp	missense	Exon 3 of 3	NP_000252.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYOC	ENST00000037502.11	TSL:1 MANE Select	c.1196G>A	p.Gly399Asp	missense	Exon 3 of 3	ENSP00000037502.5
MYOC	ENST00000638471.1	TSL:5	n.*534G>A		non_coding_transcript_exon	Exon 4 of 4	ENSP00000491206.1
MYOC	ENST00000638471.1	TSL:5	n.*534G>A		3_prime_UTR	Exon 4 of 4	ENSP00000491206.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112012

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glaucoma of childhood

Uncertain:1

Feb 15, 2023

ClinGen Glaucoma Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The c.1196G>A variant in MYOC is a missense variant predicted to cause substitution of Glycine by Aspartate at amino acid 399 (p.Gly399Asp). This variant was not found in any population of gnomAD (v2.1.1), meeting the <=0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.953, which met the >=0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with juvenile open angle glaucoma had been reported (PMID: 17562996), not meeting the >=2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 2 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PM2_Supporting.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

3.4

PhyloP100

7.8

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MutPred

0.95

Loss of sheet (P = 0.0315)

MVP

0.99

MPC

0.82

ClinPred

1.0

GERP RS

5.3

Varity_R

0.95

gMVP

0.91

Mutation Taster

=6/94

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over