chr9-114402892-G-T

Variant names:

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.2586C>A(p.His862Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,613,778 control chromosomes in the GnomAD database, including 160 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H862H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0031 ( 20 hom., cov: 33)

Exomes 𝑓: 0.0021 ( 140 hom. )

Consequence

WHRN
NM_015404.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.189

Publications

11 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=0.0032904446).

BP6

Variant 9-114402892-G-T is Benign according to our data. Variant chr9-114402892-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0716 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WHRN	NM_015404.4	MANE Select	c.2586C>A	p.His862Gln	missense	Exon 12 of 12	NP_056219.3
WHRN	NM_001173425.2		c.2583C>A	p.His861Gln	missense	Exon 12 of 12	NP_001166896.1
WHRN	NM_001346890.1		c.1533C>A	p.His511Gln	missense	Exon 8 of 8	NP_001333819.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WHRN	ENST00000362057.4	TSL:1 MANE Select	c.2586C>A	p.His862Gln	missense	Exon 12 of 12	ENSP00000354623.3
WHRN	ENST00000265134.10	TSL:1	c.1437C>A	p.His479Gln	missense	Exon 12 of 12	ENSP00000265134.6
WHRN	ENST00000866780.1		c.2583C>A	p.His861Gln	missense	Exon 12 of 12	ENSP00000536839.1

Frequencies

GnomAD3 genomes

AF:

0.00311

AC:

474

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0777

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00648

AC:

1607

AN:

247822

AF XY:

0.00604

show subpopulations

Gnomad AFR exome

AF:

0.000683

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0823

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.00311

GnomAD4 exome

AF:

0.00210

AC:

3071

AN:

1461444

Hom.:

140

Cov.:

AF XY:

0.00204

AC XY:

1486

AN XY:

727028

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33476

American (AMR)

AF:

0.000246

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0627

AC:

2488

AN:

39688

South Asian (SAS)

AF:

0.00153

AC:

132

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53142

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000423

AC:

AN:

1111938

Other (OTH)

AF:

0.00631

AC:

381

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

187

375

562

750

937

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.00311

AC:

474

AN:

152334

Hom.:

Cov.:

AF XY:

0.00345

AC XY:

257

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000553

AC:

AN:

41592

American (AMR)

AF:

0.00137

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0779

AC:

403

AN:

5172

South Asian (SAS)

AF:

0.00248

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68028

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00226

Hom.:

Bravo

AF:

0.00363

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00581

AC:

706

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Autosomal recessive nonsyndromic hearing loss 31 (1)

not provided (1)

Usher syndrome type 2D (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.52

CADD

Benign

9.5

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.055

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.49

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0033

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.58

PhyloP100

0.19

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.58

REVEL

Benign

0.11

Sift

Benign

0.31

Sift4G

Benign

0.75

Polyphen

0.55

Vest4

0.28

MutPred

0.84

Loss of sheet (P = 0.1158)

MVP

0.12

MPC

0.14

ClinPred

0.010

GERP RS

0.57

Varity_R

0.43

gMVP

0.46

Mutation Taster

=87/13

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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