1-215786825-T-G

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.10232A>C(p.Glu3411Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.538 in 1,613,422 control chromosomes in the GnomAD database, including 235,006 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 25969 hom., cov: 31)

Exomes 𝑓: 0.53 ( 209037 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 2.96

Publications

46 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=3.6495892E-6).

BP6

Variant 1-215786825-T-G is Benign according to our data. Variant chr1-215786825-T-G is described in ClinVar as Benign. ClinVar VariationId is 48344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.677 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206933.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.10232A>C	p.Glu3411Ala	missense	Exon 52 of 72	NP_996816.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.10232A>C	p.Glu3411Ala	missense	Exon 52 of 72	ENSP00000305941.3
	USH2A	ENST00000674083.1		c.10232A>C	p.Glu3411Ala	missense	Exon 52 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes

AF:

0.580

AC:

88021

AN:

151814

Hom.:

25934

Cov.:

show subpopulations

Gnomad AFR

AF:

0.683

Gnomad AMI

AF:

0.591

Gnomad AMR

AF:

0.579

Gnomad ASJ

AF:

0.527

Gnomad EAS

AF:

0.633

Gnomad SAS

AF:

0.493

Gnomad FIN

AF:

0.559

Gnomad MID

AF:

0.525

Gnomad NFE

AF:

0.525

Gnomad OTH

AF:

0.586

GnomAD2 exomes

AF:

0.548

AC:

137379

AN:

250598

AF XY:

0.543

show subpopulations

Gnomad AFR exome

AF:

0.687

Gnomad AMR exome

AF:

0.575

Gnomad ASJ exome

AF:

0.534

Gnomad EAS exome

AF:

0.634

Gnomad FIN exome

AF:

0.552

Gnomad NFE exome

AF:

0.521

Gnomad OTH exome

AF:

0.547

GnomAD4 exome

AF:

0.533

AC:

779652

AN:

1461490

Hom.:

209037

Cov.:

AF XY:

0.532

AC XY:

387031

AN XY:

727052

show subpopulations

African (AFR)

AF:

0.694

AC:

23232

AN:

33466

American (AMR)

AF:

0.568

AC:

25389

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.533

AC:

13924

AN:

26126

East Asian (EAS)

AF:

0.632

AC:

25100

AN:

39690

South Asian (SAS)

AF:

0.496

AC:

42822

AN:

86254

European-Finnish (FIN)

AF:

0.552

AC:

29421

AN:

53334

Middle Eastern (MID)

AF:

0.577

AC:

3327

AN:

5766

European-Non Finnish (NFE)

AF:

0.525

AC:

583654

AN:

1111822

Other (OTH)

AF:

0.543

AC:

32783

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

21906

43813

65719

87626

109532

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16908

33816

50724

67632

84540

<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:

0.580

AC:

88111

AN:

151932

Hom.:

25969

Cov.:

AF XY:

0.581

AC XY:

43104

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.684

AC:

28335

AN:

41436

American (AMR)

AF:

0.579

AC:

8831

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.527

AC:

1827

AN:

3466

East Asian (EAS)

AF:

0.633

AC:

3259

AN:

5148

South Asian (SAS)

AF:

0.493

AC:

2378

AN:

4820

European-Finnish (FIN)

AF:

0.559

AC:

5899

AN:

10558

Middle Eastern (MID)

AF:

0.534

AC:

157

AN:

294

European-Non Finnish (NFE)

AF:

0.525

AC:

35657

AN:

67940

Other (OTH)

AF:

0.585

AC:

1231

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1886

3772

5657

7543

9429

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

740

1480

2220

2960

3700

<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:

0.542

Hom.:

90084

Bravo

AF:

0.586

TwinsUK

AF:

0.533

AC:

1977

ALSPAC

AF:

0.526

AC:

2029

ESP6500AA

AF:

0.672

AC:

2959

ESP6500EA

AF:

0.519

AC:

4462

ExAC

AF:

0.547

AC:

66335

Asia WGS

AF:

0.558

AC:

1939

AN:

3476

EpiCase

AF:

0.526

EpiControl

AF:

0.534

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Feb 02, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Caucasian data = 3655/7020 (ESP data)

Jul 05, 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.

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 06, 2013

Eurofins Ntd Llc (ga)

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

Apr 16, 2023

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

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

Usher syndrome type 2A

Benign:3

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.036

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.14

DEOGEN2

Benign

0.020

Eigen

Benign

-1.2

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.38

MetaRNN

Benign

0.0000037

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-2.0

PhyloP100

3.0

PrimateAI

Benign

0.35

PROVEAN

Benign

2.3

REVEL

Benign

0.086

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.076

MPC

0.031

ClinPred

0.0064

GERP RS

4.9

Varity_R

0.033

gMVP

0.44

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over