rs45583140

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.9373T>C(p.Phe3125Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0501 in 1,612,768 control chromosomes in the GnomAD database, including 3,770 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F3125S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.045 ( 328 hom., cov: 33)

Exomes 𝑓: 0.051 ( 3442 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18O:1

Conservation

PhyloP100: 5.75

Publications

19 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:

LOC124902446 (HGNC:):

LOC124902446 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=0.0020181537).

BP6

Variant 10-71812008-T-C is Benign according to our data. Variant chr10-71812008-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.9373T>C	p.Phe3125Leu	missense_variant	Exon 66 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.9373T>C	p.Phe3125Leu	missense_variant	Exon 66 of 70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.0453

AC:

6853

AN:

151384

Hom.:

328

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00978

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0726

Gnomad ASJ

AF:

0.0464

Gnomad EAS

AF:

0.248

Gnomad SAS

AF:

0.0917

Gnomad FIN

AF:

0.0943

Gnomad MID

AF:

0.0128

Gnomad NFE

AF:

0.0352

Gnomad OTH

AF:

0.0421

GnomAD2 exomes

AF:

0.0739

AC:

18420

AN:

249186

AF XY:

0.0702

show subpopulations

Gnomad AFR exome

AF:

0.00949

Gnomad AMR exome

AF:

0.129

Gnomad ASJ exome

AF:

0.0466

Gnomad EAS exome

AF:

0.251

Gnomad FIN exome

AF:

0.0930

Gnomad NFE exome

AF:

0.0358

Gnomad OTH exome

AF:

0.0574

GnomAD4 exome

AF:

0.0506

AC:

73952

AN:

1461266

Hom.:

3442

Cov.:

AF XY:

0.0506

AC XY:

36816

AN XY:

726924

show subpopulations

African (AFR)

AF:

0.00720

AC:

241

AN:

33474

American (AMR)

AF:

0.125

AC:

5609

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.0469

AC:

1224

AN:

26114

East Asian (EAS)

AF:

0.277

AC:

10978

AN:

39686

South Asian (SAS)

AF:

0.0769

AC:

6636

AN:

86256

European-Finnish (FIN)

AF:

0.0898

AC:

4794

AN:

53370

Middle Eastern (MID)

AF:

0.0192

AC:

111

AN:

5768

European-Non Finnish (NFE)

AF:

0.0367

AC:

40817

AN:

1111550

Other (OTH)

AF:

0.0587

AC:

3542

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

4205

8410

12615

16820

21025

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1792

3584

5376

7168

8960

<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:

0.0452

AC:

6852

AN:

151502

Hom.:

328

Cov.:

AF XY:

0.0501

AC XY:

3710

AN XY:

74014

show subpopulations

African (AFR)

AF:

0.00975

AC:

402

AN:

41224

American (AMR)

AF:

0.0725

AC:

1104

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.0464

AC:

161

AN:

3468

East Asian (EAS)

AF:

0.248

AC:

1270

AN:

5116

South Asian (SAS)

AF:

0.0920

AC:

443

AN:

4814

European-Finnish (FIN)

AF:

0.0943

AC:

985

AN:

10440

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0351

AC:

2386

AN:

67894

Other (OTH)

AF:

0.0427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

327

654

981

1308

1635

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

270

360

450

<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:

0.0418

Hom.:

978

Bravo

AF:

0.0444

TwinsUK

AF:

0.0383

AC:

142

ALSPAC

AF:

0.0394

AC:

152

ESP6500AA

AF:

0.0106

AC:

ESP6500EA

AF:

0.0326

AC:

271

ExAC

AF:

0.0696

AC:

8411

Asia WGS

AF:

0.167

AC:

580

AN:

3478

EpiCase

AF:

0.0346

EpiControl

AF:

0.0324

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Nov 08, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 02, 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. -

Jun 12, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Retinitis pigmentosa-deafness syndrome

Benign:2

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Atypical Gaucher Disease

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Combined PSAP deficiency

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

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

- -

Galactosylceramide beta-galactosidase deficiency

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hearing loss, autosomal recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Metachromatic leukodystrophy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.013

T;T;.;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Benign

0.59

LIST_S2

Uncertain

0.87

D;D;D;D

MetaRNN

Benign

0.0020

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

.;L;.;.

PhyloP100

5.7

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.38

.;.;.;N

REVEL

Benign

0.11

Sift

Benign

0.094

.;.;.;T

Sift4G

Uncertain

0.011

D;.;D;D

Polyphen

0.90

.;P;.;.

Vest4

0.66

MutPred

0.60

Loss of stability (P = 0.1003);Loss of stability (P = 0.1003);.;.;

MPC

0.17

ClinPred

0.015

GERP RS

5.8

Varity_R

0.45

gMVP

0.68

Mutation Taster

=85/15

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over