chr10-71439838-C-T

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.7C>T(p.Arg3Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0403 in 1,563,838 control chromosomes in the GnomAD database, including 5,378 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. R3H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.12 ( 2655 hom., cov: 33)

Exomes 𝑓: 0.032 ( 2723 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: -0.134

Publications

11 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=0.00406006).

BP6

Variant 10-71439838-C-T is Benign according to our data. Variant chr10-71439838-C-T is described in ClinVar as [Benign]. Clinvar id is 46042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.7C>T	p.Arg3Cys	missense_variant	Exon 2 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.7C>T	p.Arg3Cys	missense_variant	Exon 2 of 70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.116

AC:

17618

AN:

151998

Hom.:

2644

Cov.:

show subpopulations

Gnomad AFR

AF:

0.346

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0567

Gnomad ASJ

AF:

0.0334

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.0549

Gnomad FIN

AF:

0.0194

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0240

Gnomad OTH

AF:

0.0945

GnomAD2 exomes

AF:

0.0455

AC:

8039

AN:

176796

AF XY:

0.0417

show subpopulations

Gnomad AFR exome

AF:

0.348

Gnomad AMR exome

AF:

0.0306

Gnomad ASJ exome

AF:

0.0356

Gnomad EAS exome

AF:

0.00101

Gnomad FIN exome

AF:

0.0210

Gnomad NFE exome

AF:

0.0242

Gnomad OTH exome

AF:

0.0427

GnomAD4 exome

AF:

0.0321

AC:

45367

AN:

1411720

Hom.:

2723

Cov.:

AF XY:

0.0317

AC XY:

22140

AN XY:

697690

show subpopulations

African (AFR)

AF:

0.353

AC:

11293

AN:

31994

American (AMR)

AF:

0.0336

AC:

1267

AN:

37672

Ashkenazi Jewish (ASJ)

AF:

0.0354

AC:

896

AN:

25316

East Asian (EAS)

AF:

0.000269

AC:

AN:

37222

South Asian (SAS)

AF:

0.0490

AC:

3923

AN:

80098

European-Finnish (FIN)

AF:

0.0230

AC:

1158

AN:

50354

Middle Eastern (MID)

AF:

0.0851

AC:

485

AN:

5698

European-Non Finnish (NFE)

AF:

0.0217

AC:

23561

AN:

1084912

Other (OTH)

AF:

0.0475

AC:

2774

AN:

58454

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

Heterozygous variant carriers

1625

3250

4876

6501

8126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.116

AC:

17676

AN:

152118

Hom.:

2655

Cov.:

AF XY:

0.113

AC XY:

8383

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.346

AC:

14336

AN:

41422

American (AMR)

AF:

0.0567

AC:

867

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0334

AC:

116

AN:

3472

East Asian (EAS)

AF:

0.00174

AC:

AN:

5176

South Asian (SAS)

AF:

0.0543

AC:

262

AN:

4828

European-Finnish (FIN)

AF:

0.0194

AC:

206

AN:

10606

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0240

AC:

1634

AN:

68004

Other (OTH)

AF:

0.0935

AC:

197

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

615

1230

1846

2461

3076

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0563

Hom.:

2060

Bravo

AF:

0.128

TwinsUK

AF:

0.0235

AC:

ALSPAC

AF:

0.0223

AC:

ESP6500AA

AF:

0.326

AC:

1330

ESP6500EA

AF:

0.0242

AC:

202

ExAC

AF:

0.0389

AC:

4607

Asia WGS

AF:

0.0470

AC:

165

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4Other:1

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 23, 2018

Athena Diagnostics

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

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

- -

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

- -

not specified

Benign:1

Jun 02, 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 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

0.087

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.021

T;T;T;.;.;T;.

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.73

T;T;T;T;T;T;T

MetaRNN

Benign

0.0041

T;T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

.;.;N;N;.;.;.

PhyloP100

-0.13

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.060

N;.;N;.;N;.;.

REVEL

Benign

0.077

Sift

Benign

0.068

T;.;T;.;T;.;.

Sift4G

Benign

0.20

T;T;T;T;T;T;.

Polyphen

0.0

.;.;B;B;.;.;.

Vest4

0.061

ClinPred

0.013

GERP RS

0.54

PromoterAI

-0.24

Neutral

(source)

Varity_R

0.089

gMVP

0.46

Mutation Taster

=98/2

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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chr10-71439838-C-T

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