rs17712523

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 45960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71777857-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
CDH23	NM_022124.6 linkuse as main transcript	c.5023G>A	p.Val1675Ile	missense_variant	39/70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.5023G>A	p.Val1675Ile	missense_variant	39/70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

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

GnomAD3 exomes

AF:

0.179

AC:

44689

AN:

249182

Hom.:

4295

AF XY:

0.183

AC XY:

24700

AN XY:

135162

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 SAS exome

AF:

0.193

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

Gnomad4 AFR exome

AF:

0.0307

Gnomad4 AMR exome

AF:

0.142

Gnomad4 ASJ exome

AF:

0.182

Gnomad4 EAS exome

AF:

0.145

Gnomad4 SAS exome

AF:

0.193

Gnomad4 FIN exome

AF:

0.240

Gnomad4 NFE exome

AF:

0.206

Gnomad4 OTH exome

AF:

0.179

GnomAD4 genome

AF:

0.147

AC:

22394

AN:

152066

Hom.:

2097

Cov.:

AF XY:

0.147

AC XY:

10925

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0359

Gnomad4 AMR

AF:

0.127

Gnomad4 ASJ

AF:

0.189

Gnomad4 EAS

AF:

0.153

Gnomad4 SAS

AF:

0.179

Gnomad4 FIN

AF:

0.242

Gnomad4 NFE

AF:

0.201

Gnomad4 OTH

AF:

0.141

Alfa

AF:

0.186

Hom.:

6060

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 12, 2009	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 11, 2016	- -

Usher syndrome type 1D

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Usher syndrome type 1

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over