rs696723

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_206933.4(USH2A):c.2137G>C(p.Gly713Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0202 in 1,613,916 control chromosomes in the GnomAD database, including 1,434 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G713G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.058 ( 655 hom., cov: 32)

Exomes 𝑓: 0.016 ( 779 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.51

Publications

30 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 -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0021301508).

BP6

Variant 1-216250933-C-G is Benign according to our data. Variant chr1-216250933-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.2137G>C	p.Gly713Arg	missense_variant	Exon 12 of 72	ENST00000307340.8	NP_996816.3	O75445-1
USH2A	NM_007123.6 link	c.2137G>C	p.Gly713Arg	missense_variant	Exon 12 of 21		NP_009054.6	O75445-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
USH2A	ENST00000307340.8 link	c.2137G>C	p.Gly713Arg	missense_variant	Exon 12 of 72	1	NM_206933.4	ENSP00000305941.3	O75445-1
USH2A	ENST00000366942.3 link	c.2137G>C	p.Gly713Arg	missense_variant	Exon 12 of 21	1		ENSP00000355909.3	O75445-2
USH2A	ENST00000674083.1 link	c.2137G>C	p.Gly713Arg	missense_variant	Exon 12 of 73			ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0576

AC:

8754

AN:

152066

Hom.:

654

Cov.:

show subpopulations

Gnomad AFR

AF:

0.176

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0277

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0205

Gnomad FIN

AF:

0.00632

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0105

Gnomad OTH

AF:

0.0444

GnomAD2 exomes

AF:

0.0232

AC:

5814

AN:

250936

AF XY:

0.0207

show subpopulations

Gnomad AFR exome

AF:

0.181

Gnomad AMR exome

AF:

0.0144

Gnomad ASJ exome

AF:

0.0187

Gnomad EAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00689

Gnomad NFE exome

AF:

0.0112

Gnomad OTH exome

AF:

0.0193

GnomAD4 exome

AF:

0.0163

AC:

23891

AN:

1461732

Hom.:

779

Cov.:

AF XY:

0.0159

AC XY:

11536

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.185

AC:

6196

AN:

33480

American (AMR)

AF:

0.0162

AC:

724

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0178

AC:

466

AN:

26128

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39640

South Asian (SAS)

AF:

0.0209

AC:

1802

AN:

86256

European-Finnish (FIN)

AF:

0.00618

AC:

330

AN:

53408

Middle Eastern (MID)

AF:

0.0293

AC:

169

AN:

5766

European-Non Finnish (NFE)

AF:

0.0115

AC:

12793

AN:

1111944

Other (OTH)

AF:

0.0233

AC:

1409

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

1281

2562

3842

5123

6404

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

610

1220

1830

2440

3050

<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:

0.0576

AC:

8765

AN:

152184

Hom.:

655

Cov.:

AF XY:

0.0563

AC XY:

4186

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.176

AC:

7301

AN:

41476

American (AMR)

AF:

0.0277

AC:

423

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0170

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.0205

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00632

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0105

AC:

716

AN:

68018

Other (OTH)

AF:

0.0440

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

373

746

1119

1492

1865

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<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:

0.0186

Hom.:

Bravo

AF:

0.0655

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.174

AC:

768

ESP6500EA

AF:

0.0113

AC:

ExAC

AF:

0.0256

AC:

3104

Asia WGS

AF:

0.0310

AC:

107

AN:

3478

EpiCase

AF:

0.0105

EpiControl

AF:

0.0129

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5Other:1

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

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: 30245029, 15325563, 15241801, 22952768, 27884173, 10909849, 21228398, 22004887, 20981092, 21738395, 14676276, 22025579, 12112664, 25262649) -

Feb 15, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely 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

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:4

Feb 26, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 18, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 19, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 2A

Benign:4

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Benign - Stand Alone, for Usher syndrome 2A (autosomal recessive, mild), in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS4 => Lack of segregation in affected members of a family (PMID:15325563). BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -

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

- -

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. -

Retinitis pigmentosa 39

Benign:1

Nov 04, 2023

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa

Benign:1

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.43

T;.

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Pathogenic

3.8

H;H

PhyloP100

5.5

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-6.7

D;D

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.34

MPC

0.25

ClinPred

0.057

GERP RS

4.2

Varity_R

0.84

gMVP

0.91

Mutation Taster

=65/35

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