rs41277210

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_206933.4(USH2A):c.6875G>A(p.Arg2292His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,613,568 control chromosomes in the GnomAD database, including 781 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2292C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.020 ( 48 hom., cov: 32)

Exomes 𝑓: 0.028 ( 733 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 0.0800

Publications

19 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002261877).

BP6

Variant 1-215970707-C-T is Benign according to our data. Variant chr1-215970707-C-T is described in ClinVar as Benign. ClinVar VariationId is 48571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0195 (2972/152152) while in subpopulation NFE AF = 0.0288 (1956/67996). AF 95% confidence interval is 0.0277. There are 48 homozygotes in GnomAd4. There are 1454 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 48 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.6875G>A	p.Arg2292His	missense_variant	Exon 36 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.6875G>A	p.Arg2292His	missense_variant	Exon 36 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.6875G>A	p.Arg2292His	missense_variant	Exon 36 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0195

AC:

2972

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00507

Gnomad AMI

AF:

0.0910

Gnomad AMR

AF:

0.00820

Gnomad ASJ

AF:

0.0109

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.0139

Gnomad FIN

AF:

0.0433

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0288

Gnomad OTH

AF:

0.0139

GnomAD2 exomes

AF:

0.0214

AC:

5374

AN:

251062

AF XY:

0.0222

show subpopulations

Gnomad AFR exome

AF:

0.00455

Gnomad AMR exome

AF:

0.00606

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0442

Gnomad NFE exome

AF:

0.0303

Gnomad OTH exome

AF:

0.0212

GnomAD4 exome

AF:

0.0276

AC:

40391

AN:

1461416

Hom.:

733

Cov.:

AF XY:

0.0271

AC XY:

19675

AN XY:

727002

show subpopulations

African (AFR)

AF:

0.00383

AC:

128

AN:

33442

American (AMR)

AF:

0.00654

AC:

292

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00976

AC:

255

AN:

26120

East Asian (EAS)

AF:

0.000302

AC:

AN:

39688

South Asian (SAS)

AF:

0.0159

AC:

1371

AN:

86256

European-Finnish (FIN)

AF:

0.0441

AC:

2353

AN:

53412

Middle Eastern (MID)

AF:

0.00659

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0311

AC:

34521

AN:

1111684

Other (OTH)

AF:

0.0235

AC:

1421

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

2124

4249

6373

8498

10622

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1294

2588

3882

5176

6470

<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:

0.0195

AC:

2972

AN:

152152

Hom.:

Cov.:

AF XY:

0.0195

AC XY:

1454

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.00506

AC:

210

AN:

41532

American (AMR)

AF:

0.00818

AC:

125

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

AN:

3472

East Asian (EAS)

AF:

0.000581

AC:

AN:

5162

South Asian (SAS)

AF:

0.0141

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0433

AC:

458

AN:

10584

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0288

AC:

1956

AN:

67996

Other (OTH)

AF:

0.0137

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

153

306

458

611

764

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0249

Hom.:

Bravo

AF:

0.0167

TwinsUK

AF:

0.0280

AC:

104

ALSPAC

AF:

0.0353

AC:

136

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.0303

AC:

261

ExAC

AF:

0.0224

AC:

2719

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0256

EpiControl

AF:

0.0240

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Sep 20, 2018

Athena Diagnostics

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

- -

not specified

Benign:2

Jun 24, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 17, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Usher syndrome type 2A

Benign:2

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 04, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa 39

Benign:1

Nov 04, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.90

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.022

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.55

PhyloP100

0.080

PrimateAI

Benign

0.20

PROVEAN

Benign

1.0

REVEL

Benign

0.056

Sift

Benign

0.61

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.044

MPC

0.034

ClinPred

0.0022

GERP RS

0.79

Varity_R

0.027

gMVP

0.26

Mutation Taster

=92/8

polymorphism (auto)

(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