rs10466026

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_022124.6(CDH23):c.6130G>A(p.Glu2044Lys) variant causes a missense change. The variant allele was found at a frequency of 0.289 in 1,612,844 control chromosomes in the GnomAD database, including 70,502 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 6533 hom., cov: 32)

Exomes 𝑓: 0.29 ( 63969 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 3.85

Publications

41 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011279583).

BP6

Variant 10-71791212-G-A is Benign according to our data. Variant chr10-71791212-G-A is described in ClinVar as Benign. ClinVar VariationId is 46002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.6130G>A	p.Glu2044Lys	missense_variant	Exon 47 of 70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.6130G>A	p.Glu2044Lys	missense_variant	Exon 47 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes

AF:

0.286

AC:

43472

AN:

152008

Hom.:

6526

Cov.:

show subpopulations

Gnomad AFR

AF:

0.265

Gnomad AMI

AF:

0.383

Gnomad AMR

AF:

0.332

Gnomad ASJ

AF:

0.213

Gnomad EAS

AF:

0.533

Gnomad SAS

AF:

0.243

Gnomad FIN

AF:

0.348

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.266

Gnomad OTH

AF:

0.269

GnomAD2 exomes

AF:

0.309

AC:

76554

AN:

247484

AF XY:

0.297

show subpopulations

Gnomad AFR exome

AF:

0.264

Gnomad AMR exome

AF:

0.428

Gnomad ASJ exome

AF:

0.210

Gnomad EAS exome

AF:

0.529

Gnomad FIN exome

AF:

0.349

Gnomad NFE exome

AF:

0.269

Gnomad OTH exome

AF:

0.280

GnomAD4 exome

AF:

0.289

AC:

421828

AN:

1460718

Hom.:

63969

Cov.:

AF XY:

0.284

AC XY:

206636

AN XY:

726558

show subpopulations

African (AFR)

AF:

0.268

AC:

8952

AN:

33458

American (AMR)

AF:

0.418

AC:

18615

AN:

44532

Ashkenazi Jewish (ASJ)

AF:

0.212

AC:

5535

AN:

26122

East Asian (EAS)

AF:

0.575

AC:

22811

AN:

39660

South Asian (SAS)

AF:

0.227

AC:

19563

AN:

86106

European-Finnish (FIN)

AF:

0.347

AC:

18490

AN:

53290

Middle Eastern (MID)

AF:

0.161

AC:

930

AN:

5768

European-Non Finnish (NFE)

AF:

0.279

AC:

309557

AN:

1111446

Other (OTH)

AF:

0.288

AC:

17375

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

16621

33242

49863

66484

83105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10692

21384

32076

42768

53460

<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:

0.286

AC:

43495

AN:

152126

Hom.:

6533

Cov.:

AF XY:

0.290

AC XY:

21542

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.265

AC:

11010

AN:

41508

American (AMR)

AF:

0.332

AC:

5072

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.213

AC:

739

AN:

3472

East Asian (EAS)

AF:

0.534

AC:

2756

AN:

5164

South Asian (SAS)

AF:

0.243

AC:

1174

AN:

4826

European-Finnish (FIN)

AF:

0.348

AC:

3691

AN:

10594

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.266

AC:

18107

AN:

67972

Other (OTH)

AF:

0.266

AC:

560

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1601

3202

4804

6405

8006

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

446

892

1338

1784

2230

<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:

0.272

Hom.:

14382

Bravo

AF:

0.290

TwinsUK

AF:

0.290

AC:

1076

ALSPAC

AF:

0.280

AC:

1079

ESP6500AA

AF:

0.270

AC:

1189

ESP6500EA

AF:

0.263

AC:

2258

ExAC

AF:

0.300

AC:

36393

Asia WGS

AF:

0.348

AC:

1212

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Jan 30, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 1D

Benign:2

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. -

Jul 01, 2021

Genome-Nilou Lab

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 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

- -

Retinitis pigmentosa-deafness syndrome

Benign:1

May 28, 2019

Mendelics

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

0.070

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.014

T;T

Eigen

Benign

-0.072

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.69

T;T

MetaRNN

Benign

0.0011

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.72

.;N

PhyloP100

3.8

PrimateAI

Uncertain

0.51

REVEL

Benign

0.18

Sift4G

Uncertain

0.041

D;.

Polyphen

0.64

.;P

Vest4

0.48

ClinPred

0.022

GERP RS

5.9

Varity_R

0.13

gMVP

0.64

Mutation Taster

=78/22

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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