rs114402911

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.6240G>T(p.Lys2080Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00703 in 1,613,826 control chromosomes in the GnomAD database, including 61 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K2080E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0073 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0070 ( 52 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:15

Conservation

PhyloP100: 0.412

Publications

18 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008006275).

BP6

Variant 1-216046516-C-A is Benign according to our data. Variant chr1-216046516-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.6240G>T	p.Lys2080Asn	missense_variant	Exon 32 of 72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.6240G>T	p.Lys2080Asn	missense_variant	Exon 32 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.6240G>T	p.Lys2080Asn	missense_variant	Exon 32 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.00730

AC:

1111

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00952

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00956

Gnomad ASJ

AF:

0.00750

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00734

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00556

AC:

1396

AN:

251140

AF XY:

0.00520

show subpopulations

Gnomad AFR exome

AF:

0.0102

Gnomad AMR exome

AF:

0.00509

Gnomad ASJ exome

AF:

0.00655

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00203

Gnomad NFE exome

AF:

0.00780

Gnomad OTH exome

AF:

0.00702

GnomAD4 exome

AF:

0.00700

AC:

10236

AN:

1461610

Hom.:

Cov.:

AF XY:

0.00680

AC XY:

4946

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.00974

AC:

326

AN:

33468

American (AMR)

AF:

0.00479

AC:

214

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00742

AC:

194

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.000881

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00198

AC:

106

AN:

53414

Middle Eastern (MID)

AF:

0.00677

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00798

AC:

8874

AN:

1111798

Other (OTH)

AF:

0.00674

AC:

407

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

593

1186

1779

2372

2965

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

336

672

1008

1344

1680

<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:

0.00730

AC:

1111

AN:

152216

Hom.:

Cov.:

AF XY:

0.00708

AC XY:

527

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00949

AC:

394

AN:

41530

American (AMR)

AF:

0.00955

AC:

146

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00750

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00179

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00734

AC:

499

AN:

67998

Other (OTH)

AF:

0.00805

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

107

161

214

268

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:

0.00724

Hom.:

Bravo

AF:

0.00775

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.0113

AC:

ESP6500EA

AF:

0.00930

AC:

ExAC

AF:

0.00592

AC:

719

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00834

EpiControl

AF:

0.00771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 20, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25412400, 18273898) -

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 21, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 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:5

May 14, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Lys2080Asn in Exon 32 of USH2A: This variant is not expected to have clinical si gnificance because it has been identified in 1.1% (41/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs114402911). As expected, this variant has b een reported in equal frequencies in cases and controls (Booij 2010, Clark 2010, Dreyer 2008, McGee 2010). -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 05, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 08, 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.6240G>T (p.Lys2080Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0056 in 251140 control chromosomes, predominantly at a frequency of 0.01 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. This frequency is almost close to that estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.0056 vs 0.011), supporting a benign outcome. To our knowledge, no penetrant association of c.6240G>T in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a predominant consensus as benign/likely benign. 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

- -

Usher syndrome type 2A

Benign:3

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 04, 2023

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa

Uncertain:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

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

0.22

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.067

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0080

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

0.41

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.6

REVEL

Benign

0.11

Sift

Benign

0.041

Sift4G

Uncertain

0.013

Polyphen

0.88

Vest4

0.087

MutPred

0.47

Loss of methylation at K2080 (P = 3e-04);

MVP

0.87

MPC

0.046

ClinPred

0.025

GERP RS

0.71

Varity_R

0.12

gMVP

0.42

Mutation Taster

=85/15

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