NM_206933.4:c.2522C>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The p.Ser841Tyr variant in the USH2A gene has been identified in three individuals with Usher syndrome (PMIDs 19683999, 28944237, 28653555); however, in two of those individuals a variant on the second allele was not identified (PMIDs 19683999, 28944237) and in one (PMID 28653555), the variant found on the other alleles (p.Tyr1992Cys) did not have evidence to support pathogenicity and has a high allele frequency in gnomAD (of European (Finnish) chromosomes). The filtering allele frequency of the p.Ser841Tyr variant in the USH2A gene is 1.4% for European (Finnish) chromosomes by gnomAD (1144/128242 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA248655/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.0054 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0071 ( 53 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:1U:4B:16

Conservation

PhyloP100: 3.95

Variant links:

Genes affected

USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

USH2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.2522C>A	p.Ser841Tyr	missense_variant	Exon 13 of 72	ENST00000307340.8	NP_996816.3	O75445-1
USH2A	NM_007123.6 link	c.2522C>A	p.Ser841Tyr	missense_variant	Exon 13 of 21		NP_009054.6	O75445-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
USH2A	ENST00000307340.8 link	c.2522C>A	p.Ser841Tyr	missense_variant	Exon 13 of 72	1	NM_206933.4	ENSP00000305941.3	O75445-1
USH2A	ENST00000366942.3 link	c.2522C>A	p.Ser841Tyr	missense_variant	Exon 13 of 21	1		ENSP00000355909.3	O75445-2
USH2A	ENST00000674083.1 link	c.2522C>A	p.Ser841Tyr	missense_variant	Exon 13 of 73			ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes

AF:

0.00541

AC:

824

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00426

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0139

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00780

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00606

AC:

1517

AN:

250428

Hom.:

AF XY:

0.00608

AC XY:

822

AN XY:

135306

show subpopulations

Gnomad AFR exome

AF:

0.00191

Gnomad AMR exome

AF:

0.000926

Gnomad ASJ exome

AF:

0.000796

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00111

Gnomad FIN exome

AF:

0.0156

Gnomad NFE exome

AF:

0.00912

Gnomad OTH exome

AF:

0.00752

GnomAD4 exome

AF:

0.00706

AC:

10316

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00686

AC XY:

4990

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00128

Gnomad4 AMR exome

AF:

0.00127

Gnomad4 ASJ exome

AF:

0.000918

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00136

Gnomad4 FIN exome

AF:

0.0140

Gnomad4 NFE exome

AF:

0.00806

Gnomad4 OTH exome

AF:

0.00578

GnomAD4 genome

AF:

0.00542

AC:

825

AN:

152332

Hom.:

Cov.:

AF XY:

0.00526

AC XY:

392

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00147

Gnomad4 AMR

AF:

0.00425

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0139

Gnomad4 NFE

AF:

0.00779

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00659

Hom.:

Bravo

AF:

0.00471

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00698

AC:

ExAC

AF:

0.00628

AC:

763

Asia WGS

AF:

0.000578

AC:

AN:

3476

EpiCase

AF:

0.00622

EpiControl

AF:

0.00705

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Uncertain:4Benign:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:7

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 02, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 32581362, 32707200, 30872814, 30245029, 28944237, 28653555, 28041643, 25773295, 19683999, 22004887, 25262649) -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

USH2A: BP4, BS2 -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 24, 2020

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1Benign:5

Apr 04, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: USH2A c.2522C>A (p.Ser841Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0061 in 250428 control chromosomes, including 9 homozygotes. This frequency is not higher than the estimated maximum expected (MPAF) for a pathogenic variant in USH2A causing Usher Syndrome (0.011), however the presence of homozygotes suggests a benign role for the variant. In addition, the variant is reported in certain subpopulations with even higher frequencies, e.g. in the Finnish (0.016) and Swedish (0.015), which are above the MPAF, indicating that the variant is benign. Although the variant, c.2522C>A, has been reported to be found in individuals affected with Usher Syndrome related phenotypes (HGMD), the Deafness Variation Database (DVD), classified the variant as benign, based on ethnic-specific minor allele frequencies (Shearer_2014, Azaiez_2018). To our knowledge no experimental evidence demonstrating the variant impact on protein function have been reported. 12 submitters, including an expert panel (ClinGen Hearing Loss Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as likely pathogenic (n=1), VUS (n=4), likely benign (n=2) / benign (n=5; including the expert panel). Based on the evidence outlined above, the variant was classified as benign. -

Feb 05, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 17, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not expected to have clinical significance due to an equal occur rence in probands and controls (Pennings 2004). -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Retinitis pigmentosa

Pathogenic:1Benign:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hearing impairment

Uncertain:2

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

- -

Oct 08, 2018

Center for Statistical Genetics, Columbia University

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

- -

Usher syndrome type 2A

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 30, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Progressive cone dystrophy (without rod involvement)

Uncertain:1

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

- -

Usher syndrome

Benign:1

Dec 24, 2020

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The p.Ser841Tyr variant in the USH2A gene has been identified in three individuals with Usher syndrome (PMIDs 19683999, 28944237, 28653555); however, in two of those individuals a variant on the second allele was not identified (PMIDs 19683999, 28944237) and in one (PMID 28653555), the variant found on the other alleles (p.Tyr1992Cys) did not have evidence to support pathogenicity and has a high allele frequency in gnomAD (of European (Finnish) chromosomes). The filtering allele frequency of the p.Ser841Tyr variant in the USH2A gene is 1.4% for European (Finnish) chromosomes by gnomAD (1144/128242 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.095

T;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.76

T;T

MetaRNN

Benign

0.0097

T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.5

L;L

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.6

D;D

REVEL

Uncertain

0.43

Sift

Uncertain

0.0050

D;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.61

MVP

0.97

MPC

0.25

ClinPred

0.025

GERP RS

6.0

Varity_R

0.17

gMVP

0.75

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