rs17712523

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.5023G>A(p.Val1675Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,613,690 control chromosomes in the GnomAD database, including 31,390 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 (★★). Synonymous variant affecting the same amino acid position (i.e. V1675V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.15 ( 2097 hom., cov: 31)

Exomes 𝑓: 0.20 ( 29293 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.115

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:

ENSG00000306531 (HGNC:):

ENSG00000306531 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=0.0020249784).

BP6

Variant 10-71777857-G-A is Benign according to our data. Variant chr10-71777857-G-A is described in ClinVar as Benign. ClinVar VariationId is 45960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.5023G>A	p.Val1675Ile	missense_variant	Exon 39 of 70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CDH23	ENST00000224721.12 link	c.5023G>A	p.Val1675Ile	missense_variant	Exon 39 of 70	5	NM_022124.6	ENSP00000224721.9
ENSG00000306531	ENST00000819235.1 link	n.158-792C>T		intron_variant	Intron 1 of 1
ENSG00000306531	ENST00000819236.1 link	n.157-689C>T		intron_variant	Intron 1 of 1
ENSG00000306531	ENST00000819237.1 link	n.146-787C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.147

AC:

22398

AN:

151948

Hom.:

2097

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0360

Gnomad AMI

AF:

0.113

Gnomad AMR

AF:

0.128

Gnomad ASJ

AF:

0.189

Gnomad EAS

AF:

0.154

Gnomad SAS

AF:

0.180

Gnomad FIN

AF:

0.242

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.201

Gnomad OTH

AF:

0.136

GnomAD2 exomes

AF:

0.179

AC:

44689

AN:

249182

AF XY:

0.183

show subpopulations

Gnomad AFR exome

AF:

0.0329

Gnomad AMR exome

AF:

0.144

Gnomad ASJ exome

AF:

0.183

Gnomad EAS exome

AF:

0.160

Gnomad FIN exome

AF:

0.231

Gnomad NFE exome

AF:

0.200

Gnomad OTH exome

AF:

0.171

GnomAD4 exome

AF:

0.197

AC:

288436

AN:

1461624

Hom.:

29293

Cov.:

AF XY:

0.197

AC XY:

143288

AN XY:

727086

show subpopulations

African (AFR)

AF:

0.0307

AC:

1027

AN:

33480

American (AMR)

AF:

0.142

AC:

6344

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.182

AC:

4756

AN:

26136

East Asian (EAS)

AF:

0.145

AC:

5743

AN:

39698

South Asian (SAS)

AF:

0.193

AC:

16665

AN:

86252

European-Finnish (FIN)

AF:

0.240

AC:

12797

AN:

53380

Middle Eastern (MID)

AF:

0.169

AC:

976

AN:

5768

European-Non Finnish (NFE)

AF:

0.206

AC:

229340

AN:

1111820

Other (OTH)

AF:

0.179

AC:

10788

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

14005

28010

42014

56019

70024

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8038

16076

24114

32152

40190

<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:

0.147

AC:

22394

AN:

152066

Hom.:

2097

Cov.:

AF XY:

0.147

AC XY:

10925

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.0359

AC:

1490

AN:

41494

American (AMR)

AF:

0.127

AC:

1943

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.189

AC:

657

AN:

3472

East Asian (EAS)

AF:

0.153

AC:

791

AN:

5154

South Asian (SAS)

AF:

0.179

AC:

860

AN:

4816

European-Finnish (FIN)

AF:

0.242

AC:

2554

AN:

10562

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.201

AC:

13640

AN:

67986

Other (OTH)

AF:

0.141

AC:

297

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

943

1886

2829

3772

4715

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

250

500

750

1000

1250

<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:

0.178

Hom.:

8556

Bravo

AF:

0.134

TwinsUK

AF:

0.198

AC:

735

ALSPAC

AF:

0.204

AC:

785

ESP6500AA

AF:

0.0390

AC:

171

ESP6500EA

AF:

0.193

AC:

1654

ExAC

AF:

0.178

AC:

21619

Asia WGS

AF:

0.176

AC:

613

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:3Other:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Apr 11, 2016

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

- -

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

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

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

0.067

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.75

CADD

Benign

4.7

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0065

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.68

T;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

.;L

PhyloP100

0.12

PrimateAI

Benign

0.24

REVEL

Benign

0.014

Sift4G

Benign

0.57

T;.

Polyphen

0.0010

.;B

Vest4

0.051

ClinPred

0.0028

GERP RS

-1.2

Varity_R

0.021

gMVP

0.29

Mutation Taster

=93/7

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