rs4747194

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_022124.6(CDH23):c.7073G>A(p.Arg2358Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 1,613,004 control chromosomes in the GnomAD database, including 71,697 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2358W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.29 ( 6585 hom., cov: 33)

Exomes 𝑓: 0.29 ( 65112 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.850

Publications

38 publications found

Variant links:

Genes affected

CDH23 (HGNC:13733): (cadherin related 23) This gene is a member of the cadherin superfamily, whose genes encode calcium dependent cell-cell adhesion glycoproteins. The encoded protein is thought to be involved in stereocilia organization and hair bundle formation. The gene is located in a region containing the human deafness loci DFNB12 and USH1D. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of this cadherin-like gene. Upregulation of this gene may also be associated with breast cancer. Alternative splice variants encoding different isoforms have been described. [provided by RefSeq, May 2013]

CDH23 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 12
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Usher syndrome type 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 1D
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CDH23 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 10-71799129-G-A is Benign according to our data. Variant chr10-71799129-G-A is described in ClinVar as Benign. ClinVar VariationId is 46026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CDH23	NM_022124.6 link	c.7073G>A	p.Arg2358Gln	missense_variant	Exon 51 of 70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171933.1 link	c.353G>A	p.Arg118Gln	missense_variant	Exon 4 of 23		NP_001165404.1
CDH23	NM_001171934.1 link	c.353G>A	p.Arg118Gln	missense_variant	Exon 4 of 22		NP_001165405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.7073G>A	p.Arg2358Gln	missense_variant	Exon 51 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes

AF:

0.288

AC:

43751

AN:

151980

Hom.:

6581

Cov.:

show subpopulations

Gnomad AFR

AF:

0.267

Gnomad AMI

AF:

0.384

Gnomad AMR

AF:

0.332

Gnomad ASJ

AF:

0.222

Gnomad EAS

AF:

0.532

Gnomad SAS

AF:

0.271

Gnomad FIN

AF:

0.346

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.267

Gnomad OTH

AF:

0.269

GnomAD2 exomes

AF:

0.315

AC:

78310

AN:

248704

AF XY:

0.304

show subpopulations

Gnomad AFR exome

AF:

0.268

Gnomad AMR exome

AF:

0.431

Gnomad ASJ exome

AF:

0.221

Gnomad EAS exome

AF:

0.530

Gnomad FIN exome

AF:

0.347

Gnomad NFE exome

AF:

0.270

Gnomad OTH exome

AF:

0.286

GnomAD4 exome

AF:

0.292

AC:

426043

AN:

1460906

Hom.:

65112

Cov.:

AF XY:

0.288

AC XY:

209353

AN XY:

726744

show subpopulations

African (AFR)

AF:

0.268

AC:

8984

AN:

33464

American (AMR)

AF:

0.420

AC:

18759

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.223

AC:

5834

AN:

26114

East Asian (EAS)

AF:

0.575

AC:

22836

AN:

39684

South Asian (SAS)

AF:

0.256

AC:

22111

AN:

86228

European-Finnish (FIN)

AF:

0.345

AC:

18408

AN:

53376

Middle Eastern (MID)

AF:

0.174

AC:

1005

AN:

5768

European-Non Finnish (NFE)

AF:

0.279

AC:

310514

AN:

1111218

Other (OTH)

AF:

0.291

AC:

17592

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

14164

28329

42493

56658

70822

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10736

21472

32208

42944

53680

<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:

0.288

AC:

43770

AN:

152098

Hom.:

6585

Cov.:

AF XY:

0.292

AC XY:

21672

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.267

AC:

11089

AN:

41488

American (AMR)

AF:

0.332

AC:

5084

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.222

AC:

770

AN:

3470

East Asian (EAS)

AF:

0.532

AC:

2743

AN:

5152

South Asian (SAS)

AF:

0.270

AC:

1304

AN:

4824

European-Finnish (FIN)

AF:

0.346

AC:

3663

AN:

10576

Middle Eastern (MID)

AF:

0.139

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.267

AC:

18165

AN:

67980

Other (OTH)

AF:

0.266

AC:

562

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1616

3232

4849

6465

8081

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

448

896

1344

1792

2240

<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:

0.275

Hom.:

23525

Bravo

AF:

0.292

TwinsUK

AF:

0.291

AC:

1078

ALSPAC

AF:

0.281

AC:

1084

ESP6500AA

AF:

0.263

AC:

1060

ESP6500EA

AF:

0.261

AC:

2191

ExAC

AF:

0.307

AC:

37081

Asia WGS

AF:

0.364

AC:

1267

AN:

3478

EpiCase

AF:

0.256

EpiControl

AF:

0.258

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Feb 27, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 12, 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

Jan 08, 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.

Usher syndrome type 1D

Benign:2

Jul 01, 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.

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 12

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Usher syndrome type 1

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.010

T;T;.;.

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.71

T;T;T;T

MetaRNN

Benign

0.00033

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;L;.;.

PhyloP100

0.85

PrimateAI

Benign

0.22

PROVEAN

Benign

0.0

.;.;.;N

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;.;T

Sift4G

Benign

0.16

T;.;T;T

Vest4

0.044

ClinPred

0.026

GERP RS

2.7

Varity_R

0.19

gMVP

0.34

Mutation Taster

=84/16

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.49

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.49

Position offset: 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