1-215741484-T-C

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.11602A>G(p.Met3868Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,613,586 control chromosomes in the GnomAD database, including 38,998 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M3868L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.21 ( 3492 hom., cov: 31)

Exomes 𝑓: 0.22 ( 35506 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.26

Publications

40 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=0.0016642809).

BP6

Variant 1-215741484-T-C is Benign according to our data. Variant chr1-215741484-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.229 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.11602A>G	p.Met3868Val	missense	Exon 60 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.11602A>G	p.Met3868Val	missense	Exon 60 of 72	ENSP00000305941.3
	USH2A	ENST00000674083.1		c.11602A>G	p.Met3868Val	missense	Exon 60 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes

AF:

0.210

AC:

31814

AN:

151834

Hom.:

3494

Cov.:

show subpopulations

Gnomad AFR

AF:

0.190

Gnomad AMI

AF:

0.230

Gnomad AMR

AF:

0.218

Gnomad ASJ

AF:

0.197

Gnomad EAS

AF:

0.107

Gnomad SAS

AF:

0.0813

Gnomad FIN

AF:

0.233

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.232

Gnomad OTH

AF:

0.235

GnomAD2 exomes

AF:

0.196

AC:

49194

AN:

251298

AF XY:

0.194

show subpopulations

Gnomad AFR exome

AF:

0.190

Gnomad AMR exome

AF:

0.199

Gnomad ASJ exome

AF:

0.200

Gnomad EAS exome

AF:

0.0936

Gnomad FIN exome

AF:

0.237

Gnomad NFE exome

AF:

0.229

Gnomad OTH exome

AF:

0.214

GnomAD4 exome

AF:

0.217

AC:

317029

AN:

1461636

Hom.:

35506

Cov.:

AF XY:

0.213

AC XY:

155180

AN XY:

727104

show subpopulations

African (AFR)

AF:

0.192

AC:

6425

AN:

33478

American (AMR)

AF:

0.203

AC:

9060

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.201

AC:

5244

AN:

26128

East Asian (EAS)

AF:

0.136

AC:

5382

AN:

39680

South Asian (SAS)

AF:

0.100

AC:

8661

AN:

86226

European-Finnish (FIN)

AF:

0.241

AC:

12852

AN:

53354

Middle Eastern (MID)

AF:

0.211

AC:

1215

AN:

5768

European-Non Finnish (NFE)

AF:

0.230

AC:

255565

AN:

1111900

Other (OTH)

AF:

0.209

AC:

12625

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

13434

26869

40303

53738

67172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8640

17280

25920

34560

43200

<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:

0.209

AC:

31826

AN:

151950

Hom.:

3492

Cov.:

AF XY:

0.207

AC XY:

15354

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.190

AC:

7855

AN:

41434

American (AMR)

AF:

0.218

AC:

3330

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.197

AC:

685

AN:

3470

East Asian (EAS)

AF:

0.107

AC:

553

AN:

5150

South Asian (SAS)

AF:

0.0817

AC:

394

AN:

4820

European-Finnish (FIN)

AF:

0.233

AC:

2455

AN:

10556

Middle Eastern (MID)

AF:

0.231

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.232

AC:

15788

AN:

67944

Other (OTH)

AF:

0.232

AC:

488

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1266

2533

3799

5066

6332

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

320

640

960

1280

1600

<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:

0.211

Hom.:

6684

Bravo

AF:

0.207

TwinsUK

AF:

0.231

AC:

855

ALSPAC

AF:

0.236

AC:

911

ESP6500AA

AF:

0.190

AC:

835

ESP6500EA

AF:

0.233

AC:

2006

ExAC

AF:

0.196

AC:

23802

Asia WGS

AF:

0.108

AC:

376

AN:

3478

EpiCase

AF:

0.230

EpiControl

AF:

0.230

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 26, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 20, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 19, 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.

Apr 16, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

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

Usher syndrome type 2A

Benign:2

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

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Benign:1

Oct 25, 2021

Fulgent Genetics, Fulgent Genetics

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.0020

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.037

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.33

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.20

PhyloP100

-2.3

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.33

REVEL

Benign

0.017

Sift

Benign

1.0

Sift4G

Benign

0.71

Polyphen

0.0

Vest4

0.028

MPC

0.030

ClinPred

0.014

GERP RS

-9.7

Varity_R

0.050

gMVP

0.30

Mutation Taster

=95/5

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

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