rs146655362

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015404.4(WHRN):c.191C>A(p.Ala64Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000864 in 1,611,128 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A64S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00089 ( 2 hom. )

Consequence

WHRN
NM_015404.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 2.88

Publications

6 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, Unknown Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
autosomal recessive nonsyndromic hearing loss 31
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03975451).

BP6

Variant 9-114504611-G-T is Benign according to our data. Variant chr9-114504611-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45664.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000571 (87/152384) while in subpopulation NFE AF = 0.00113 (77/68040). AF 95% confidence interval is 0.000928. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015404.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	NM_015404.4	MANE Select	c.191C>A	p.Ala64Asp	missense	Exon 1 of 12	NP_056219.3	Q9P202-1
	WHRN	NM_001173425.2		c.191C>A	p.Ala64Asp	missense	Exon 1 of 12	NP_001166896.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WHRN	ENST00000362057.4	TSL:1 MANE Select	c.191C>A	p.Ala64Asp	missense	Exon 1 of 12	ENSP00000354623.3	Q9P202-1
WHRN	ENST00000866780.1		c.191C>A	p.Ala64Asp	missense	Exon 1 of 12	ENSP00000536839.1
WHRN	ENST00000929560.1		c.191C>A	p.Ala64Asp	missense	Exon 1 of 11	ENSP00000599619.1

Frequencies

GnomAD3 genomes

AF:

0.000571

AC:

AN:

152266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00113

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000538

AC:

129

AN:

239780

AF XY:

0.000611

show subpopulations

Gnomad AFR exome

AF:

0.0000639

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00114

Gnomad OTH exome

AF:

0.000503

GnomAD4 exome

AF:

0.000895

AC:

1305

AN:

1458744

Hom.:

Cov.:

AF XY:

0.000890

AC XY:

646

AN XY:

725728

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33452

American (AMR)

AF:

0.000202

AC:

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.00

AC:

AN:

86178

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51254

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00110

AC:

1226

AN:

1111378

Other (OTH)

AF:

0.00104

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

103

205

308

410

513

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<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:

0.000571

AC:

AN:

152384

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

74522

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41590

American (AMR)

AF:

0.000131

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00113

AC:

AN:

68040

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000824

Hom.:

Bravo

AF:

0.000782

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.000536

AC:

EpiCase

AF:

0.00153

EpiControl

AF:

0.00213

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Autosomal recessive nonsyndromic hearing loss 31 (1)

not specified (1)

Usher syndrome type 2D (1)

Usher syndrome type 2D;C1846839:Autosomal recessive nonsyndromic hearing loss 31 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.45

CADD

Pathogenic

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.059

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.014

MetaRNN

Benign

0.040

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PhyloP100

2.9

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.44

REVEL

Benign

0.13

Sift

Benign

0.24

Sift4G

Benign

0.13

Polyphen

0.20

Vest4

0.58

MVP

0.17

MPC

1.3

ClinPred

0.013

GERP RS

2.4

Varity_R

0.26

gMVP

0.60

Mutation Taster

=87/13

polymorphism

(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

Computational scores

Splicing

Publications

Other links and lift over