rs146445078

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_206933.4(USH2A):c.9203T>C(p.Val3068Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000569 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3068M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00058 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 0.494

Publications

4 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020991892).

BP6

Variant 1-215844349-A-G is Benign according to our data. Variant chr1-215844349-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48614.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.9203T>C	p.Val3068Ala	missense_variant	Exon 46 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.9203T>C	p.Val3068Ala	missense_variant	Exon 46 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.9203T>C	p.Val3068Ala	missense_variant	Exon 46 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000661

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000411

AC:

103

AN:

250692

AF XY:

0.000391

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.000724

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000579

AC:

846

AN:

1461502

Hom.:

Cov.:

AF XY:

0.000568

AC XY:

413

AN XY:

727040

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33462

American (AMR)

AF:

0.000493

AC:

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000412

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000694

AC:

772

AN:

1111818

Other (OTH)

AF:

0.000331

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

148

198

247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

112

140

<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:

0.000473

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41580

American (AMR)

AF:

0.000916

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000662

AC:

AN:

68024

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000653

Hom.:

Bravo

AF:

0.000597

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000371

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Mar 06, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in an individual with hearing loss who also harbored a nonsense variant on the same USH2A allele (in cis), however, this individual did not have an additional disease-causing variant on the opposite allele (in trans) (Tang et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25991456, 32707200, 32483926) -

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Uncertain:1

Apr 07, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Usher syndrome type 2A

Uncertain:1

Oct 01, 2021

Myriad Genetics, Inc.

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_206933.2(USH2A):c.9203T>C(V3068A) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. V3068A has been observed in cases with relevant disease (PMID: 25991456). Functional assessments of this variant are not available in the literature. V3068A has been observed in population frequency databases (gnomAD: NFE 0.07%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.9203T>C(V3068A) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

not specified

Benign:1

Aug 15, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Val3068Ala in exon 46 of USH2A: This variant is not expected to have clinical significance because of a lack of conservation across species including mammals. Of note, rat, mouse and opossum have an alanine at this position despite high n earby amino acid conservation. It has been identified in 85/126144 of European c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org; dbSNP rs146445078). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.026

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.50

M_CAP

Benign

0.034

MetaRNN

Benign

0.021

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.14

PhyloP100

0.49

PrimateAI

Benign

0.23

PROVEAN

Benign

0.090

REVEL

Benign

0.066

Sift

Benign

0.83

Sift4G

Benign

0.93

Polyphen

0.0010

Vest4

0.26

MVP

0.69

MPC

0.034

ClinPred

0.0061

GERP RS

3.7

Varity_R

0.030

gMVP

0.22

Mutation Taster

=79/21

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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