rs12339210

Variant summary

Our verdict is Benign. Variant got -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. 12/20 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:7

Conservation

PhyloP100: 5.00

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 45661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-114407961-G-C is described in Lovd as [Benign].

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/exons	MANE	UniProt
WHRN	NM_015404.4 linkuse as main transcript	c.1684C>G	p.Pro562Ala	missense_variant	8/12	ENST00000362057.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WHRN	ENST00000362057.4 linkuse as main transcript	c.1684C>G	p.Pro562Ala	missense_variant	8/12	1	NM_015404.4	P1	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

GnomAD3 exomes

AF:

0.0906

AC:

20876

AN:

230454

Hom.:

1105

AF XY:

0.0890

AC XY:

11071

AN XY:

124326

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 SAS exome

AF:

0.0343

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

Gnomad4 AFR exome

AF:

0.0206

Gnomad4 AMR exome

AF:

0.0856

Gnomad4 ASJ exome

AF:

0.125

Gnomad4 EAS exome

AF:

0.0141

Gnomad4 SAS exome

AF:

0.0374

Gnomad4 FIN exome

AF:

0.156

Gnomad4 NFE exome

AF:

0.124

Gnomad4 OTH exome

AF:

0.100

GnomAD4 genome

AF:

0.0909

AC:

13842

AN:

152264

Hom.:

818

Cov.:

AF XY:

0.0893

AC XY:

6647

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0255

Gnomad4 AMR

AF:

0.104

Gnomad4 ASJ

AF:

0.128

Gnomad4 EAS

AF:

0.0178

Gnomad4 SAS

AF:

0.0317

Gnomad4 FIN

AF:

0.160

Gnomad4 NFE

AF:

0.125

Gnomad4 OTH

AF:

0.0998

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:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 19, 2009	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Autosomal recessive nonsyndromic hearing loss 31

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Usher syndrome type 2D

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Dann

Benign

0.97

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

MutationTaster

Benign

0.00063

P;P;P

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over