rs12339210

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.1684C>G(p.Pro562Ala) variant causes a missense change. The variant allele was found at a frequency of 0.111 in 1,601,290 control chromosomes in the GnomAD database, including 10,914 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.091 ( 818 hom., cov: 33)

Exomes 𝑓: 0.11 ( 10096 hom. )

Consequence

WHRN
NM_015404.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.00

Publications

31 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=0.0017889142).

BP6

Variant 9-114407961-G-C is Benign according to our data. Variant chr9-114407961-G-C is described in ClinVar as Benign. ClinVar VariationId is 45661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WHRN	NM_015404.4 link	c.1684C>G	p.Pro562Ala	missense_variant	Exon 8 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.1684C>G	p.Pro562Ala	missense_variant	Exon 8 of 12	1	NM_015404.4	ENSP00000354623.3		Q9P202-1

Frequencies

GnomAD3 genomes

AF:

0.0909

AC:

13836

AN:

152146

Hom.:

817

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0255

Gnomad AMI

AF:

0.114

Gnomad AMR

AF:

0.104

Gnomad ASJ

AF:

0.128

Gnomad EAS

AF:

0.0177

Gnomad SAS

AF:

0.0306

Gnomad FIN

AF:

0.160

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.124

Gnomad OTH

AF:

0.101

GnomAD2 exomes

AF:

0.0906

AC:

20876

AN:

230454

AF XY:

0.0890

show subpopulations

Gnomad AFR exome

AF:

0.0208

Gnomad AMR exome

AF:

0.0810

Gnomad ASJ exome

AF:

0.122

Gnomad EAS exome

AF:

0.0145

Gnomad FIN exome

AF:

0.149

Gnomad NFE exome

AF:

0.118

Gnomad OTH exome

AF:

0.0976

GnomAD4 exome

AF:

0.113

AC:

163180

AN:

1449026

Hom.:

10096

Cov.:

AF XY:

0.110

AC XY:

79473

AN XY:

719476

show subpopulations

African (AFR)

AF:

0.0206

AC:

684

AN:

33220

American (AMR)

AF:

0.0856

AC:

3724

AN:

43490

Ashkenazi Jewish (ASJ)

AF:

0.125

AC:

3239

AN:

25868

East Asian (EAS)

AF:

0.0141

AC:

554

AN:

39290

South Asian (SAS)

AF:

0.0374

AC:

3148

AN:

84136

European-Finnish (FIN)

AF:

0.156

AC:

8193

AN:

52444

Middle Eastern (MID)

AF:

0.0833

AC:

479

AN:

5748

European-Non Finnish (NFE)

AF:

0.124

AC:

137158

AN:

1104964

Other (OTH)

AF:

0.100

AC:

6001

AN:

59866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

6818

13635

20453

27270

34088

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4898

9796

14694

19592

24490

<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:

0.0909

AC:

13842

AN:

152264

Hom.:

818

Cov.:

AF XY:

0.0893

AC XY:

6647

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0255

AC:

1060

AN:

41576

American (AMR)

AF:

0.104

AC:

1586

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.128

AC:

443

AN:

3470

East Asian (EAS)

AF:

0.0178

AC:

AN:

5180

South Asian (SAS)

AF:

0.0317

AC:

153

AN:

4826

European-Finnish (FIN)

AF:

0.160

AC:

1700

AN:

10596

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.125

AC:

8470

AN:

68018

Other (OTH)

AF:

0.0998

AC:

211

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

658

1316

1975

2633

3291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

312

468

624

780

<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:

0.114

Hom.:

798

Bravo

AF:

0.0845

TwinsUK

AF:

0.126

AC:

466

ALSPAC

AF:

0.134

AC:

515

ESP6500AA

AF:

0.0259

AC:

114

ESP6500EA

AF:

0.122

AC:

1049

ExAC

AF:

0.0814

AC:

9860

Asia WGS

AF:

0.0180

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jun 19, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 24, 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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

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

- -

Autosomal recessive nonsyndromic hearing loss 31

Benign:1

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. -

Retinitis pigmentosa-deafness syndrome

Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.10

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.24

.;.;T

Eigen

Benign

0.14

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

D;D;D

MetaRNN

Benign

0.0018

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

.;.;M

PhyloP100

5.0

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.2

N;N;N

REVEL

Benign

0.085

Sift

Uncertain

0.012

D;D;D

Sift4G

Uncertain

0.019

D;D;D

Polyphen

0.74, 0.63

.;P;P

Vest4

0.21

MPC

0.15

ClinPred

0.025

GERP RS

4.6

Varity_R

0.069

gMVP

0.31

Mutation Taster

=84/16

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