rs11592462

Variant names:

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.5996C>G(p.Thr1999Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 1,613,008 control chromosomes in the GnomAD database, including 179,488 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. T1999T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.41 ( 13508 hom., cov: 33)

Exomes 𝑓: 0.47 ( 165980 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.70

Publications

39 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=5.040169E-4).

BP6

Variant 10-71790360-C-G is Benign according to our data. Variant chr10-71790360-C-G is described in ClinVar as [Benign]. Clinvar id is 45997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.5996C>G	p.Thr1999Ser	missense_variant	Exon 46 of 70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.5996C>G	p.Thr1999Ser	missense_variant	Exon 46 of 70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.409

AC:

62191

AN:

151952

Hom.:

13501

Cov.:

show subpopulations

Gnomad AFR

AF:

0.289

Gnomad AMI

AF:

0.395

Gnomad AMR

AF:

0.368

Gnomad ASJ

AF:

0.529

Gnomad EAS

AF:

0.165

Gnomad SAS

AF:

0.512

Gnomad FIN

AF:

0.427

Gnomad MID

AF:

0.516

Gnomad NFE

AF:

0.494

Gnomad OTH

AF:

0.430

GnomAD2 exomes

AF:

0.423

AC:

104457

AN:

246988

AF XY:

0.439

show subpopulations

Gnomad AFR exome

AF:

0.279

Gnomad AMR exome

AF:

0.296

Gnomad ASJ exome

AF:

0.527

Gnomad EAS exome

AF:

0.165

Gnomad FIN exome

AF:

0.422

Gnomad NFE exome

AF:

0.487

Gnomad OTH exome

AF:

0.445

GnomAD4 exome

AF:

0.470

AC:

687244

AN:

1460938

Hom.:

165980

Cov.:

AF XY:

0.473

AC XY:

344012

AN XY:

726756

show subpopulations

African (AFR)

AF:

0.276

AC:

9254

AN:

33474

American (AMR)

AF:

0.302

AC:

13474

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.524

AC:

13686

AN:

26122

East Asian (EAS)

AF:

0.141

AC:

5602

AN:

39690

South Asian (SAS)

AF:

0.518

AC:

44665

AN:

86216

European-Finnish (FIN)

AF:

0.428

AC:

22730

AN:

53112

Middle Eastern (MID)

AF:

0.498

AC:

2872

AN:

5764

European-Non Finnish (NFE)

AF:

0.493

AC:

547463

AN:

1111530

Other (OTH)

AF:

0.456

AC:

27498

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

18170

36339

54509

72678

90848

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.409

AC:

62204

AN:

152070

Hom.:

13508

Cov.:

AF XY:

0.406

AC XY:

30193

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.288

AC:

11953

AN:

41492

American (AMR)

AF:

0.367

AC:

5604

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.529

AC:

1835

AN:

3468

East Asian (EAS)

AF:

0.165

AC:

854

AN:

5172

South Asian (SAS)

AF:

0.512

AC:

2464

AN:

4816

European-Finnish (FIN)

AF:

0.427

AC:

4506

AN:

10562

Middle Eastern (MID)

AF:

0.517

AC:

152

AN:

294

European-Non Finnish (NFE)

AF:

0.494

AC:

33562

AN:

67960

Other (OTH)

AF:

0.434

AC:

915

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1880

3760

5640

7520

9400

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.474

Hom.:

13287

Bravo

AF:

0.392

TwinsUK

AF:

0.485

AC:

1800

ALSPAC

AF:

0.495

AC:

1907

ESP6500AA

AF:

0.270

AC:

1130

ESP6500EA

AF:

0.486

AC:

4091

ExAC

AF:

0.426

AC:

51511

Asia WGS

AF:

0.331

AC:

1154

AN:

3478

EpiCase

AF:

0.500

EpiControl

AF:

0.499

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Oct 28, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31706157) -

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

- -

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 12, 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. -

Autosomal recessive nonsyndromic hearing loss 12

Benign:2

Jan 12, 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

0.088

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0059

T;T

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.59

T;T

MetaRNN

Benign

0.00050

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.39

.;N

PhyloP100

1.7

PrimateAI

Benign

0.41

REVEL

Benign

0.086

Sift4G

Benign

0.61

T;.

Polyphen

0.0

.;B

Vest4

0.16

MutPred

0.47

Gain of phosphorylation at Y1995 (P = 0.2156);Gain of phosphorylation at Y1995 (P = 0.2156);

ClinPred

0.014

GERP RS

4.1

Varity_R

0.099

gMVP

0.26

Mutation Taster

=91/9

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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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rs11592462

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