NM_206933.4:c.1931A>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_206933.4(USH2A):c.1931A>T(p.Asp644Val) variant causes a missense change. The variant allele was found at a frequency of 0.0665 in 1,613,914 control chromosomes in the GnomAD database, including 4,060 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. D644D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.050 ( 301 hom., cov: 32)

Exomes 𝑓: 0.068 ( 3759 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 6.89

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=0.007833093).

BP6

Variant 1-216289320-T-A is Benign according to our data. Variant chr1-216289320-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.1931A>T	p.Asp644Val	missense_variant	Exon 11 of 72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6 link	c.1931A>T	p.Asp644Val	missense_variant	Exon 11 of 21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
USH2A	ENST00000307340.8 link	c.1931A>T	p.Asp644Val	missense_variant	Exon 11 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000366942.3 link	c.1931A>T	p.Asp644Val	missense_variant	Exon 11 of 21	1		ENSP00000355909.3
USH2A	ENST00000674083.1 link	c.1931A>T	p.Asp644Val	missense_variant	Exon 11 of 73			ENSP00000501296.1

Frequencies

GnomAD3 genomes

AF:

0.0505

AC:

7682

AN:

152136

Hom.:

302

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0144

Gnomad AMI

AF:

0.0768

Gnomad AMR

AF:

0.0490

Gnomad ASJ

AF:

0.125

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.0583

Gnomad FIN

AF:

0.0282

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.0742

Gnomad OTH

AF:

0.0709

GnomAD2 exomes

AF:

0.0581

AC:

14602

AN:

251344

AF XY:

0.0613

show subpopulations

Gnomad AFR exome

AF:

0.0114

Gnomad AMR exome

AF:

0.0389

Gnomad ASJ exome

AF:

0.133

Gnomad EAS exome

AF:

0.000599

Gnomad FIN exome

AF:

0.0273

Gnomad NFE exome

AF:

0.0776

Gnomad OTH exome

AF:

0.0770

GnomAD4 exome

AF:

0.0681

AC:

99598

AN:

1461660

Hom.:

3759

Cov.:

AF XY:

0.0692

AC XY:

50311

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.0127

AC:

426

AN:

33474

American (AMR)

AF:

0.0409

AC:

1829

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.130

AC:

3409

AN:

26128

East Asian (EAS)

AF:

0.000504

AC:

AN:

39676

South Asian (SAS)

AF:

0.0586

AC:

5055

AN:

86252

European-Finnish (FIN)

AF:

0.0325

AC:

1735

AN:

53416

Middle Eastern (MID)

AF:

0.144

AC:

829

AN:

5768

European-Non Finnish (NFE)

AF:

0.0737

AC:

81922

AN:

1111838

Other (OTH)

AF:

0.0724

AC:

4373

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

5640

11280

16920

22560

28200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2988

5976

8964

11952

14940

<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:

0.0505

AC:

7683

AN:

152254

Hom.:

301

Cov.:

AF XY:

0.0485

AC XY:

3612

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0144

AC:

597

AN:

41572

American (AMR)

AF:

0.0490

AC:

749

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.125

AC:

435

AN:

3470

East Asian (EAS)

AF:

0.000965

AC:

AN:

5182

South Asian (SAS)

AF:

0.0592

AC:

285

AN:

4816

European-Finnish (FIN)

AF:

0.0282

AC:

299

AN:

10612

Middle Eastern (MID)

AF:

0.160

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0742

AC:

5048

AN:

67994

Other (OTH)

AF:

0.0702

AC:

148

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

378

756

1135

1513

1891

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<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:

0.0737

Hom.:

381

Bravo

AF:

0.0507

TwinsUK

AF:

0.0677

AC:

251

ALSPAC

AF:

0.0680

AC:

262

ESP6500AA

AF:

0.0154

AC:

ESP6500EA

AF:

0.0836

AC:

719

ExAC

AF:

0.0577

AC:

7008

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.0909

EpiControl

AF:

0.0879

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 19, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 02, 2011

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 2A

Benign:3

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2Other:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Benign:1

Nov 03, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely 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

- -

Retinitis pigmentosa

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.24

T;.

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D

MetaRNN

Benign

0.0078

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.8

M;M

PhyloP100

6.9

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-2.8

D;D

REVEL

Uncertain

0.31

Sift

Benign

0.35

T;T

Sift4G

Uncertain

0.024

D;D

Polyphen

0.64

P;B

Vest4

0.23

MPC

0.040

ClinPred

0.035

GERP RS

5.4

Varity_R

0.16

gMVP

0.73

Mutation Taster

=88/12

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