rs2274159

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_015404.4(WHRN):c.2348T>C(p.Val783Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 1,610,410 control chromosomes in the GnomAD database, including 191,166 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V783E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.41 ( 14062 hom., cov: 32)

Exomes 𝑓: 0.49 ( 177104 hom. )

Consequence

WHRN
NM_015404.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.944

Publications

50 publications found

Variant links:

Genes affected

WHRN (HGNC:16361): (whirlin) This gene is thought to function in the organization and stabilization of sterocilia elongation and actin cystoskeletal assembly, based on studies of the related mouse gene. Mutations in this gene have been associated with autosomal recessive non-syndromic deafness and Usher Syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

WHRN Gene-Disease associations (from GenCC):

Usher syndrome type 2D
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
autosomal recessive nonsyndromic hearing loss 31
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Usher syndrome type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

WHRN 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=4.0899216E-5).

BP6

Variant 9-114403966-A-G is Benign according to our data. Variant chr9-114403966-A-G is described in ClinVar as Benign. ClinVar VariationId is 45672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WHRN	NM_015404.4 link	c.2348T>C	p.Val783Ala	missense_variant	Exon 10 of 12	ENST00000362057.4	NP_056219.3	Q9P202-1B9EGE6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WHRN	ENST00000362057.4 link	c.2348T>C	p.Val783Ala	missense_variant	Exon 10 of 12	1	NM_015404.4	ENSP00000354623.3		Q9P202-1

Frequencies

GnomAD3 genomes

AF:

0.414

AC:

62811

AN:

151658

Hom.:

14055

Cov.:

show subpopulations

Gnomad AFR

AF:

0.221

Gnomad AMI

AF:

0.499

Gnomad AMR

AF:

0.449

Gnomad ASJ

AF:

0.601

Gnomad EAS

AF:

0.464

Gnomad SAS

AF:

0.515

Gnomad FIN

AF:

0.478

Gnomad MID

AF:

0.519

Gnomad NFE

AF:

0.491

Gnomad OTH

AF:

0.449

GnomAD2 exomes

AF:

0.481

AC:

120111

AN:

249582

AF XY:

0.489

show subpopulations

Gnomad AFR exome

AF:

0.215

Gnomad AMR exome

AF:

0.494

Gnomad ASJ exome

AF:

0.597

Gnomad EAS exome

AF:

0.454

Gnomad FIN exome

AF:

0.468

Gnomad NFE exome

AF:

0.497

Gnomad OTH exome

AF:

0.494

GnomAD4 exome

AF:

0.490

AC:

714533

AN:

1458632

Hom.:

177104

Cov.:

AF XY:

0.493

AC XY:

357504

AN XY:

725716

show subpopulations

African (AFR)

AF:

0.210

AC:

7025

AN:

33478

American (AMR)

AF:

0.491

AC:

21956

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.596

AC:

15580

AN:

26136

East Asian (EAS)

AF:

0.503

AC:

19974

AN:

39694

South Asian (SAS)

AF:

0.540

AC:

46537

AN:

86252

European-Finnish (FIN)

AF:

0.468

AC:

23590

AN:

50422

Middle Eastern (MID)

AF:

0.542

AC:

3127

AN:

5768

European-Non Finnish (NFE)

AF:

0.493

AC:

547856

AN:

1111784

Other (OTH)

AF:

0.478

AC:

28888

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

22724

45447

68171

90894

113618

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16040

32080

48120

64160

80200

<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:

0.414

AC:

62835

AN:

151778

Hom.:

14062

Cov.:

AF XY:

0.413

AC XY:

30639

AN XY:

74164

show subpopulations

African (AFR)

AF:

0.221

AC:

9165

AN:

41432

American (AMR)

AF:

0.449

AC:

6849

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.601

AC:

2083

AN:

3466

East Asian (EAS)

AF:

0.464

AC:

2365

AN:

5098

South Asian (SAS)

AF:

0.518

AC:

2481

AN:

4794

European-Finnish (FIN)

AF:

0.478

AC:

5045

AN:

10558

Middle Eastern (MID)

AF:

0.527

AC:

154

AN:

292

European-Non Finnish (NFE)

AF:

0.491

AC:

33302

AN:

67856

Other (OTH)

AF:

0.444

AC:

937

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

1587

3174

4761

6348

7935

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

598

1196

1794

2392

2990

<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:

0.468

Hom.:

53500

Bravo

AF:

0.406

TwinsUK

AF:

0.489

AC:

1814

ALSPAC

AF:

0.506

AC:

1950

ESP6500AA

AF:

0.237

AC:

1043

ESP6500EA

AF:

0.500

AC:

4299

ExAC

AF:

0.479

AC:

58101

Asia WGS

AF:

0.414

AC:

1440

AN:

3478

EpiCase

AF:

0.496

EpiControl

AF:

0.502

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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

- -

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: 29083408) -

not specified

Benign:2

Jun 19, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 31

Benign:2

Jan 12, 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 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 2D

Benign:1

Jan 12, 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

0.054

BayesDel_addAF

Benign

-0.86

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.50

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.050

.;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0013

LIST_S2

Benign

0.12

T;T;T

MetaRNN

Benign

0.000041

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.7

.;.;N

PhyloP100

0.94

PrimateAI

Benign

0.33

PROVEAN

Benign

0.72

N;N;N

REVEL

Benign

0.032

Sift

Benign

1.0

T;T;T

Sift4G

Benign

0.52

T;T;T

Polyphen

0.0

.;B;B

Vest4

0.020

MPC

0.15

ClinPred

0.00058

GERP RS

1.1

Varity_R

0.019

gMVP

0.13

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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