1-216246872-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

25 publications found

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 Gene-Disease associations (from GenCC):

Usher syndrome type 2
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 2A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
retinitis pigmentosa 39
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

USH2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206933.4. 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
	USH2A	NM_206933.4	MANE Select	c.2522C>A	p.Ser841Tyr	missense	Exon 13 of 72	NP_996816.3
	USH2A	NM_007123.6		c.2522C>A	p.Ser841Tyr	missense	Exon 13 of 21	NP_009054.6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
USH2A	ENST00000307340.8	TSL:1 MANE Select	c.2522C>A	p.Ser841Tyr	missense	Exon 13 of 72	ENSP00000305941.3
USH2A	ENST00000366942.3	TSL:1	c.2522C>A	p.Ser841Tyr	missense	Exon 13 of 21	ENSP00000355909.3
USH2A	ENST00000674083.1		c.2522C>A	p.Ser841Tyr	missense	Exon 13 of 73	ENSP00000501296.1

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

GnomAD2 exomes

AF:

0.00606

AC:

1517

AN:

250428

AF XY:

0.00608

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 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

African (AFR)

AF:

0.00128

AC:

AN:

33480

American (AMR)

AF:

0.00127

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000918

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00136

AC:

117

AN:

86258

European-Finnish (FIN)

AF:

0.0140

AC:

748

AN:

53416

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00806

AC:

8958

AN:

1111960

Other (OTH)

AF:

0.00578

AC:

349

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

697

1394

2091

2788

3485

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

326

652

978

1304

1630

<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

AF:

0.00542

AC:

825

AN:

152332

Hom.:

Cov.:

AF XY:

0.00526

AC XY:

392

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00147

AC:

AN:

41588

American (AMR)

AF:

0.00425

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00104

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0139

AC:

148

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00779

AC:

530

AN:

68030

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

145

193

241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00698

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

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Oct 02, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 24, 2020

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

USH2A: BP4, BS2

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)

not specified

Uncertain:1Benign:5

Dec 17, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Significance:Benign

Review Status:no assertion criteria provided

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

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

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).

Retinitis pigmentosa

Pathogenic:1Benign:1

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.

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Hearing impairment

Uncertain:2

Oct 08, 2018

Center for Statistical Genetics, Columbia University

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:research

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:research

Usher syndrome type 2A

Benign:2

Dec 30, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.095

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0097

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.5

PhyloP100

4.0

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.43

Sift

Uncertain

0.0050

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.61

MVP

0.97

MPC

0.25

ClinPred

0.025

GERP RS

6.0

Varity_R

0.17

gMVP

0.75

Mutation Taster

=70/30

polymorphism

(source)

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

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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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over