NM_206933.4:c.2522C>A

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

1
8
9

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]

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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
USH2ANM_206933.4 linkc.2522C>A p.Ser841Tyr missense_variant Exon 13 of 72 ENST00000307340.8 NP_996816.3 O75445-1
USH2ANM_007123.6 linkc.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 Appris UniProt
USH2AENST00000307340.8 linkc.2522C>A p.Ser841Tyr missense_variant Exon 13 of 72 1 NM_206933.4 ENSP00000305941.3 O75445-1
USH2AENST00000366942.3 linkc.2522C>A p.Ser841Tyr missense_variant Exon 13 of 21 1 ENSP00000355909.3 O75445-2
USH2AENST00000674083.1 linkc.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.:
1
Cov.:
33
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.:
9
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.:
53
Cov.:
31
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.:
1
Cov.:
33
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.:
3
Bravo
AF:
0.00471
TwinsUK
AF:
0.00998
AC:
37
ALSPAC
AF:
0.00830
AC:
32
ESP6500AA
AF:
0.00204
AC:
9
ESP6500EA
AF:
0.00698
AC:
60
ExAC
AF:
0.00628
AC:
763
Asia WGS
AF:
0.000578
AC:
2
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
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

- -

-
Clinical Genetics, Academic Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

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 -

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) -

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

- -

not specified Uncertain:1Benign:5
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). -

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

-
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

- -

Retinitis pigmentosa Pathogenic:1Benign:1
Jan 01, 2015
NIHR Bioresource Rare Diseases, University of Cambridge
Significance: Likely pathogenic
Review Status: flagged submission
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
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

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. -

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
T
BayesDel_noAF
Uncertain
-0.080
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.095
T;.
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.76
T;T
MetaRNN
Benign
0.0097
T;T
MetaSVM
Benign
-0.51
T
MutationAssessor
Benign
1.5
L;L
PrimateAI
Benign
0.40
T
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
T
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.

Other links and lift over

dbSNP: rs111033282; hg19: chr1-216420214; COSMIC: COSV56354454; API