1-216421964-C-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.373G>A(p.Ala125Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.719 in 1,613,698 control chromosomes in the GnomAD database, including 418,913 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 (★★).

Frequency

Genomes: 𝑓 0.73 ( 40885 hom., cov: 32)

Exomes 𝑓: 0.72 ( 378028 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.358

Publications

55 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=1.3263331E-6).

BP6

Variant 1-216421964-C-T is Benign according to our data. Variant chr1-216421964-C-T is described in ClinVar as Benign. ClinVar VariationId is 48507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.373G>A	p.Ala125Thr	missense_variant	Exon 2 of 72	ENST00000307340.8	NP_996816.3	O75445-1
USH2A	NM_007123.6 link	c.373G>A	p.Ala125Thr	missense_variant	Exon 2 of 21		NP_009054.6	O75445-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
USH2A	ENST00000307340.8 link	c.373G>A	p.Ala125Thr	missense_variant	Exon 2 of 72	1	NM_206933.4	ENSP00000305941.3	O75445-1
USH2A	ENST00000366942.3 link	c.373G>A	p.Ala125Thr	missense_variant	Exon 2 of 21	1		ENSP00000355909.3	O75445-2
USH2A	ENST00000674083.1 link	c.373G>A	p.Ala125Thr	missense_variant	Exon 2 of 73			ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes

AF:

0.732

AC:

111235

AN:

151902

Hom.:

40838

Cov.:

show subpopulations

Gnomad AFR

AF:

0.756

Gnomad AMI

AF:

0.792

Gnomad AMR

AF:

0.723

Gnomad ASJ

AF:

0.657

Gnomad EAS

AF:

0.832

Gnomad SAS

AF:

0.760

Gnomad FIN

AF:

0.779

Gnomad MID

AF:

0.598

Gnomad NFE

AF:

0.708

Gnomad OTH

AF:

0.695

GnomAD2 exomes

AF:

0.729

AC:

182834

AN:

250924

AF XY:

0.725

show subpopulations

Gnomad AFR exome

AF:

0.757

Gnomad AMR exome

AF:

0.730

Gnomad ASJ exome

AF:

0.658

Gnomad EAS exome

AF:

0.836

Gnomad FIN exome

AF:

0.774

Gnomad NFE exome

AF:

0.705

Gnomad OTH exome

AF:

0.700

GnomAD4 exome

AF:

0.718

AC:

1049721

AN:

1461678

Hom.:

378028

Cov.:

AF XY:

0.717

AC XY:

521325

AN XY:

727130

show subpopulations

African (AFR)

AF:

0.757

AC:

25343

AN:

33470

American (AMR)

AF:

0.731

AC:

32673

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.654

AC:

17085

AN:

26128

East Asian (EAS)

AF:

0.845

AC:

33561

AN:

39694

South Asian (SAS)

AF:

0.728

AC:

62821

AN:

86256

European-Finnish (FIN)

AF:

0.768

AC:

41027

AN:

53406

Middle Eastern (MID)

AF:

0.648

AC:

3735

AN:

5766

European-Non Finnish (NFE)

AF:

0.711

AC:

790289

AN:

1111896

Other (OTH)

AF:

0.715

AC:

43187

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

20932

41864

62795

83727

104659

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19884

39768

59652

79536

99420

<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:

0.732

AC:

111334

AN:

152020

Hom.:

40885

Cov.:

AF XY:

0.737

AC XY:

54765

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.756

AC:

31324

AN:

41454

American (AMR)

AF:

0.723

AC:

11024

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.657

AC:

2278

AN:

3466

East Asian (EAS)

AF:

0.833

AC:

4296

AN:

5158

South Asian (SAS)

AF:

0.760

AC:

3668

AN:

4824

European-Finnish (FIN)

AF:

0.779

AC:

8223

AN:

10560

Middle Eastern (MID)

AF:

0.595

AC:

175

AN:

294

European-Non Finnish (NFE)

AF:

0.708

AC:

48151

AN:

67986

Other (OTH)

AF:

0.697

AC:

1473

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1544

3088

4631

6175

7719

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

846

1692

2538

3384

4230

<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:

0.711

Hom.:

188724

Bravo

AF:

0.727

TwinsUK

AF:

0.718

AC:

2661

ALSPAC

AF:

0.710

AC:

2736

ESP6500AA

AF:

0.758

AC:

3339

ESP6500EA

AF:

0.699

AC:

6012

ExAC

AF:

0.729

AC:

88518

Asia WGS

AF:

0.788

AC:

2742

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Feb 19, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 12, 2015

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 03, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 10, 2023

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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:4

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

- -

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

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:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.019

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0065

LIST_S2

Benign

0.22

T;T

MetaRNN

Benign

0.0000013

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.9

N;N

PhyloP100

0.36

PrimateAI

Benign

0.31

PROVEAN

Benign

0.59

N;N

REVEL

Benign

0.084

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.0030

MPC

0.030

ClinPred

0.0021

GERP RS

-1.4

Varity_R

0.041

gMVP

0.24

Mutation Taster

=99/1

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