rs4747195

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.7139C>T(p.Pro2380Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.287 in 1,613,748 control chromosomes in the GnomAD database, including 70,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P2380P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.28 ( 6316 hom., cov: 33)

Exomes 𝑓: 0.29 ( 63787 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 7.88

Publications

44 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=0.003720373).

BP6

Variant 10-71799195-C-T is Benign according to our data. Variant chr10-71799195-C-T is described in ClinVar as Benign. ClinVar VariationId is 46028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.7139C>T	p.Pro2380Leu	missense_variant	Exon 51 of 70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152
CDH23	NM_001171933.1 link	c.419C>T	p.Pro140Leu	missense_variant	Exon 4 of 23		NP_001165404.1	Q9H251-7
CDH23	NM_001171934.1 link	c.419C>T	p.Pro140Leu	missense_variant	Exon 4 of 22		NP_001165405.1	Q9H251-9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.7139C>T	p.Pro2380Leu	missense_variant	Exon 51 of 70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.281

AC:

42635

AN:

151990

Hom.:

6312

Cov.:

show subpopulations

Gnomad AFR

AF:

0.248

Gnomad AMI

AF:

0.382

Gnomad AMR

AF:

0.329

Gnomad ASJ

AF:

0.213

Gnomad EAS

AF:

0.532

Gnomad SAS

AF:

0.244

Gnomad FIN

AF:

0.345

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.266

Gnomad OTH

AF:

0.260

GnomAD2 exomes

AF:

0.308

AC:

76764

AN:

249150

AF XY:

0.296

show subpopulations

Gnomad AFR exome

AF:

0.246

Gnomad AMR exome

AF:

0.428

Gnomad ASJ exome

AF:

0.210

Gnomad EAS exome

AF:

0.530

Gnomad FIN exome

AF:

0.347

Gnomad NFE exome

AF:

0.269

Gnomad OTH exome

AF:

0.281

GnomAD4 exome

AF:

0.288

AC:

421080

AN:

1461638

Hom.:

63787

Cov.:

AF XY:

0.284

AC XY:

206338

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.248

AC:

8290

AN:

33478

American (AMR)

AF:

0.417

AC:

18648

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.212

AC:

5545

AN:

26136

East Asian (EAS)

AF:

0.575

AC:

22840

AN:

39698

South Asian (SAS)

AF:

0.227

AC:

19603

AN:

86252

European-Finnish (FIN)

AF:

0.345

AC:

18411

AN:

53402

Middle Eastern (MID)

AF:

0.159

AC:

916

AN:

5768

European-Non Finnish (NFE)

AF:

0.278

AC:

309564

AN:

1111818

Other (OTH)

AF:

0.286

AC:

17263

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

16477

32954

49431

65908

82385

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10694

21388

32082

42776

53470

<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:

0.280

AC:

42650

AN:

152110

Hom.:

6316

Cov.:

AF XY:

0.284

AC XY:

21138

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.248

AC:

10295

AN:

41494

American (AMR)

AF:

0.330

AC:

5040

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.213

AC:

739

AN:

3472

East Asian (EAS)

AF:

0.532

AC:

2740

AN:

5152

South Asian (SAS)

AF:

0.244

AC:

1173

AN:

4814

European-Finnish (FIN)

AF:

0.345

AC:

3656

AN:

10584

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.266

AC:

18078

AN:

67982

Other (OTH)

AF:

0.258

AC:

545

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1572

3144

4716

6288

7860

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

438

876

1314

1752

2190

<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.:

15195

Bravo

AF:

0.284

TwinsUK

AF:

0.290

AC:

1076

ALSPAC

AF:

0.280

AC:

1080

ESP6500AA

AF:

0.240

AC:

966

ESP6500EA

AF:

0.261

AC:

2173

ExAC

AF:

0.299

AC:

36197

Asia WGS

AF:

0.348

AC:

1210

AN:

3478

EpiCase

AF:

0.253

EpiControl

AF:

0.256

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

- -

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. -

Feb 27, 2017

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

0.31

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.15

T;T;.;.

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D;D

MetaRNN

Benign

0.0037

T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Pathogenic

2.9

.;M;.;.

PhyloP100

7.9

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-9.5

.;.;.;D

REVEL

Benign

0.26

Sift

Uncertain

0.0090

.;.;.;D

Sift4G

Pathogenic

0.0

D;.;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.67

MPC

0.31

ClinPred

0.068

GERP RS

5.5

Varity_R

0.89

gMVP

0.72

Mutation Taster

=30/70

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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