rs942519

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.1838T>C(p.Met613Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 1,613,758 control chromosomes in the GnomAD database, including 234,027 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 0.49 ( 18272 hom., cov: 32)

Exomes 𝑓: 0.54 ( 215755 hom. )

Consequence

WHRN
NM_015404.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.24

Publications

45 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=6.9923813E-6).

BP6

Variant 9-114406753-A-G is Benign according to our data. Variant chr9-114406753-A-G is described in ClinVar as Benign. ClinVar VariationId is 45663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WHRN	NM_015404.4 link	c.1838T>C	p.Met613Thr	missense_variant	Exon 9 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.1838T>C	p.Met613Thr	missense_variant	Exon 9 of 12	1	NM_015404.4	ENSP00000354623.3		Q9P202-1

Frequencies

GnomAD3 genomes

AF:

0.485

AC:

73752

AN:

151974

Hom.:

18256

Cov.:

show subpopulations

Gnomad AFR

AF:

0.364

Gnomad AMI

AF:

0.570

Gnomad AMR

AF:

0.494

Gnomad ASJ

AF:

0.613

Gnomad EAS

AF:

0.505

Gnomad SAS

AF:

0.576

Gnomad FIN

AF:

0.491

Gnomad MID

AF:

0.554

Gnomad NFE

AF:

0.540

Gnomad OTH

AF:

0.500

GnomAD2 exomes

AF:

0.529

AC:

132256

AN:

249862

AF XY:

0.536

show subpopulations

Gnomad AFR exome

AF:

0.360

Gnomad AMR exome

AF:

0.520

Gnomad ASJ exome

AF:

0.607

Gnomad EAS exome

AF:

0.499

Gnomad FIN exome

AF:

0.494

Gnomad NFE exome

AF:

0.544

Gnomad OTH exome

AF:

0.533

GnomAD4 exome

AF:

0.542

AC:

791630

AN:

1461664

Hom.:

215755

Cov.:

AF XY:

0.544

AC XY:

395471

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.359

AC:

12020

AN:

33480

American (AMR)

AF:

0.519

AC:

23192

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.605

AC:

15798

AN:

26132

East Asian (EAS)

AF:

0.536

AC:

21281

AN:

39692

South Asian (SAS)

AF:

0.596

AC:

51369

AN:

86242

European-Finnish (FIN)

AF:

0.493

AC:

26316

AN:

53354

Middle Eastern (MID)

AF:

0.570

AC:

3285

AN:

5764

European-Non Finnish (NFE)

AF:

0.545

AC:

606210

AN:

1111936

Other (OTH)

AF:

0.533

AC:

32159

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

27214

54428

81642

108856

136070

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17182

34364

51546

68728

85910

<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:

0.485

AC:

73800

AN:

152094

Hom.:

18272

Cov.:

AF XY:

0.482

AC XY:

35876

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.364

AC:

15098

AN:

41482

American (AMR)

AF:

0.494

AC:

7554

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.613

AC:

2126

AN:

3470

East Asian (EAS)

AF:

0.505

AC:

2601

AN:

5148

South Asian (SAS)

AF:

0.579

AC:

2793

AN:

4826

European-Finnish (FIN)

AF:

0.491

AC:

5205

AN:

10594

Middle Eastern (MID)

AF:

0.561

AC:

165

AN:

294

European-Non Finnish (NFE)

AF:

0.540

AC:

36694

AN:

67966

Other (OTH)

AF:

0.495

AC:

1045

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1960

3920

5881

7841

9801

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

678

1356

2034

2712

3390

<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:

0.526

Hom.:

54813

Bravo

AF:

0.482

TwinsUK

AF:

0.546

AC:

2023

ALSPAC

AF:

0.559

AC:

2156

ESP6500AA

AF:

0.387

AC:

1703

ESP6500EA

AF:

0.546

AC:

4695

ExAC

AF:

0.529

AC:

64172

Asia WGS

AF:

0.479

AC:

1667

AN:

3478

EpiCase

AF:

0.541

EpiControl

AF:

0.546

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

May 31, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

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

- -

Autosomal recessive nonsyndromic hearing loss 31

Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

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. -

Usher syndrome type 2D

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

0.068

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.4

(source)

DANN

Benign

0.18

DEOGEN2

Benign

0.047

.;.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0095

LIST_S2

Benign

0.019

T;T;T

MetaRNN

Benign

0.0000070

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.69

.;.;N

PhyloP100

1.2

PrimateAI

Benign

0.26

PROVEAN

Benign

0.45

N;N;N

REVEL

Benign

0.054

Sift

Benign

0.53

T;T;T

Sift4G

Benign

0.53

T;T;T

Polyphen

0.0

.;B;B

Vest4

0.014

MPC

0.14

ClinPred

0.0037

GERP RS

0.056

Varity_R

0.042

gMVP

0.17

Mutation Taster

=100/0

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