rs56385601

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_206933.4(USH2A):c.7685T>C(p.Val2562Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00756 in 1,614,060 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2562F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0059 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0077 ( 58 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.93

Publications

22 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:

ENSG00000229242 (HGNC:):

ENSG00000229242 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010328323).

BP6

Variant 1-215888964-A-G is Benign according to our data. Variant chr1-215888964-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.7685T>C	p.Val2562Ala	missense_variant	Exon 41 of 72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
USH2A	ENST00000307340.8 link	c.7685T>C	p.Val2562Ala	missense_variant	Exon 41 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1 link	c.7685T>C	p.Val2562Ala	missense_variant	Exon 41 of 73			ENSP00000501296.1
ENSG00000229242	ENST00000414995.1 link	n.60+2323A>G		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.00587

AC:

893

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00213

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00615

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00480

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00867

Gnomad OTH

AF:

0.00909

GnomAD2 exomes

AF:

0.00649

AC:

1630

AN:

251140

AF XY:

0.00670

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.00466

Gnomad ASJ exome

AF:

0.00984

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00675

Gnomad NFE exome

AF:

0.00950

Gnomad OTH exome

AF:

0.00670

GnomAD4 exome

AF:

0.00774

AC:

11317

AN:

1461848

Hom.:

Cov.:

AF XY:

0.00788

AC XY:

5733

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

33480

American (AMR)

AF:

0.00490

AC:

219

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0116

AC:

304

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00262

AC:

226

AN:

86258

European-Finnish (FIN)

AF:

0.00614

AC:

328

AN:

53414

Middle Eastern (MID)

AF:

0.00572

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00879

AC:

9769

AN:

1111974

Other (OTH)

AF:

0.00634

AC:

383

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

677

1354

2031

2708

3385

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

344

688

1032

1376

1720

<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:

0.00587

AC:

893

AN:

152212

Hom.:

Cov.:

AF XY:

0.00563

AC XY:

419

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.00212

AC:

AN:

41522

American (AMR)

AF:

0.00614

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00291

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00480

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00867

AC:

590

AN:

68018

Other (OTH)

AF:

0.00900

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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

100

<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:

0.00826

Hom.:

Bravo

AF:

0.00593

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00860

AC:

ExAC

AF:

0.00651

AC:

790

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0106

EpiControl

AF:

0.0120

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Jan 16, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31266775, 19683999, 23484092, 18273898, 20052763, 22681893, 26927203, 22004887) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

USH2A: BP4, BS2 -

not specified

Benign:4

Jan 17, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Val2562Ala in exon 41 of USH2A: This variant has been reported in nine individua ls with a clinical diagnosis of Usher Syndrome types 1, 2 or 3 (Dreyer 2008, Jai jo 2009). However, several of these individuals already had other explanations f or their Usher syndrome (Jaijo 2009). In addition, this amino acid is not highly conserved acroos evolution, with the mouse and rat having an alanine at positio n 2562. In addition, this variant is listed in dbSNP (rs56385601 - no frequency data available) and has been identified in 6/278 (2.2%) probands tested by our l aboratory, none of whom had a variant on their second USH2A allele. In summary, this variant meets our criteria to be classified as benign. -

Sep 30, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 05, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 15, 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.7685T>C (p.Val2562Ala) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0065 in 251140 control chromosomes, predominantly at a frequency of 0.0095 within the Non-Finnish European subpopulation in the gnomAD database, including 12 homozygotes. This frequency is close to that estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.0065 vs 0.011), supporting a neutral outcome. Although reported frequently in the literature, to our knowledge, no occurrence of c.7685T>C in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. At-least one report listed this variant along with two other pathogenic alleles in an individual with Usher syndrome, supporting a benign outcome (example, Hagag_2020). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Usher syndrome type 2A

Benign:2

Nov 04, 2023

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 23, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Retinitis pigmentosa 39

Benign:1

Nov 04, 2023

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.085

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.55

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

PhyloP100

1.9

PrimateAI

Benign

0.29

PROVEAN

Benign

-2.1

REVEL

Benign

0.10

Sift

Benign

0.79

Sift4G

Benign

0.21

Polyphen

0.0040

Vest4

0.71

MVP

0.84

MPC

0.037

ClinPred

0.0040

GERP RS

3.5

Varity_R

0.058

gMVP

0.25

Mutation Taster

=95/5

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over