chr1-171636386-C-T

Position:

chr1-171636386-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1054G>A variant in MYOC is a missense variant predicted to cause substitution of Glutamic Acid by Lysine at amino acid 352 (p.Glu352Lys). The highest minor allele frequency of this variant was in the African/African-American population of gnomAD (v2.1.1) = 0.01174, which met the ≥ 0.01 threshold set for BA1 (293 alleles out of 24 954, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.514, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. Previous studies (PMIDs: 16466712, 10545602) demonstrated that the Glu352Lys protein had similar solubility and secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. As BA1 was met, PP1 did not apply and segregations were not counted. Although probands with 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 primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BA1, BS3_Moderate LINK:https://erepo.genome.network/evrepo/ui/classification/CA1244087/MONDO:0007665/019

Frequency

Genomes: 𝑓 0.0038 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 5 hom. )

Consequence

MYOC
NM_000261.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:8

Conservation

PhyloP100: 4.08

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 -9 ACMG points.

BS3

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.1054G>A	p.Glu352Lys	missense_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.1054G>A	p.Glu352Lys	missense_variant	3/3	1	NM_000261.2	ENSP00000037502.5	Q99972
MYOCOS	ENST00000637303.1 linkuse as main transcript	c.235-2244C>T		intron_variant		5		ENSP00000490048.1	A0A1B0GUC4
MYOC	ENST00000638471.1 linkuse as main transcript	n.*392G>A		non_coding_transcript_exon_variant	4/4	5		ENSP00000491206.1	A0A1W2PP09
MYOC	ENST00000638471.1 linkuse as main transcript	n.*392G>A		3_prime_UTR_variant	4/4	5		ENSP00000491206.1	A0A1W2PP09

Frequencies

GnomAD3 genomes

AF:

0.00370

AC:

563

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0126

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.000931

AC:

234

AN:

251390

Hom.:

AF XY:

0.000662

AC XY:

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.0119

Gnomad AMR exome

AF:

0.000954

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000425

AC:

622

AN:

1461808

Hom.:

Cov.:

AF XY:

0.000374

AC XY:

272

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0136

Gnomad4 AMR exome

AF:

0.000939

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000495

Gnomad4 OTH exome

AF:

0.00103

GnomAD4 genome

AF:

0.00378

AC:

575

AN:

152178

Hom.:

Cov.:

AF XY:

0.00379

AC XY:

282

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0129

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.000545

Hom.:

Bravo

AF:

0.00426

ESP6500AA

AF:

0.0125

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00119

AC:

145

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2020	This variant is associated with the following publications: (PMID: 30484747, 9804137, 16466712) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	MYOC: BS1 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 07, 2023	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

Glaucoma 1, open angle, A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Glaucoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Glaucoma 1, open angle, E

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Glaucoma Variant Curation Expert Panel

Mar 05, 2022

The c.1054G>A variant in MYOC is a missense variant predicted to cause substitution of Glutamic Acid by Lysine at amino acid 352 (p.Glu352Lys). The highest minor allele frequency of this variant was in the African/African-American population of gnomAD (v2.1.1) = 0.01174, which met the >= 0.01 threshold set for BA1 (293 alleles out of 24 954, meeting the threshold of >= 5 of at least 2,000 observed alleles). The REVEL score = 0.514, which was neither above nor below the thresholds for PP3 (>= 0.7) or BP4 (<= 0.15), predicting a damaging or benign impact on MYOC function. Previous studies (PMIDs: 16466712, 10545602) demonstrated that the Glu352Lys protein had similar solubility and secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. As BA1 was met, PP1 did not apply and segregations were not counted. Although probands with 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 primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BA1, BS3_Moderate -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

Eigen

Benign

0.14

Eigen_PC

Benign

0.038

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.86

MetaRNN

Benign

0.013

MetaSVM

Uncertain

0.58

MutationAssessor

Benign

1.8

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.51

Sift

Benign

0.030

Sift4G

Benign

0.092

Polyphen

1.0

Vest4

0.53

MVP

0.95

MPC

0.76

ClinPred

0.024

GERP RS

4.8

Varity_R

0.47

gMVP

0.90

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