rs4747194

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_022124.6(CDH23):c.7073G>A(p.Arg2358Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 1,613,004 control chromosomes in the GnomAD database, including 71,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 6585 hom., cov: 33)

Exomes 𝑓: 0.29 ( 65112 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.850

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 -16 ACMG points.

BP6

Variant 10-71799129-G-A is Benign according to our data. Variant chr10-71799129-G-A is described in ClinVar as [Benign]. Clinvar id is 46026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71799129-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.7073G>A	p.Arg2358Gln	missense_variant	51/70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152
CDH23	NM_001171933.1 link	c.353G>A	p.Arg118Gln	missense_variant	4/23		NP_001165404.1	Q9H251-7
CDH23	NM_001171934.1 link	c.353G>A	p.Arg118Gln	missense_variant	4/22		NP_001165405.1	Q9H251-9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.7073G>A	p.Arg2358Gln	missense_variant	51/70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.288

AC:

43751

AN:

151980

Hom.:

6581

Cov.:

show subpopulations

Gnomad AFR

AF:

0.267

Gnomad AMI

AF:

0.384

Gnomad AMR

AF:

0.332

Gnomad ASJ

AF:

0.222

Gnomad EAS

AF:

0.532

Gnomad SAS

AF:

0.271

Gnomad FIN

AF:

0.346

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.267

Gnomad OTH

AF:

0.269

GnomAD3 exomes

AF:

0.315

AC:

78310

AN:

248704

Hom.:

13346

AF XY:

0.304

AC XY:

40964

AN XY:

134910

show subpopulations

Gnomad AFR exome

AF:

0.268

Gnomad AMR exome

AF:

0.431

Gnomad ASJ exome

AF:

0.221

Gnomad EAS exome

AF:

0.530

Gnomad SAS exome

AF:

0.259

Gnomad FIN exome

AF:

0.347

Gnomad NFE exome

AF:

0.270

Gnomad OTH exome

AF:

0.286

GnomAD4 exome

AF:

0.292

AC:

426043

AN:

1460906

Hom.:

65112

Cov.:

AF XY:

0.288

AC XY:

209353

AN XY:

726744

show subpopulations

Gnomad4 AFR exome

AF:

0.268

Gnomad4 AMR exome

AF:

0.420

Gnomad4 ASJ exome

AF:

0.223

Gnomad4 EAS exome

AF:

0.575

Gnomad4 SAS exome

AF:

0.256

Gnomad4 FIN exome

AF:

0.345

Gnomad4 NFE exome

AF:

0.279

Gnomad4 OTH exome

AF:

0.291

GnomAD4 genome

AF:

0.288

AC:

43770

AN:

152098

Hom.:

6585

Cov.:

AF XY:

0.292

AC XY:

21672

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.267

Gnomad4 AMR

AF:

0.332

Gnomad4 ASJ

AF:

0.222

Gnomad4 EAS

AF:

0.532

Gnomad4 SAS

AF:

0.270

Gnomad4 FIN

AF:

0.346

Gnomad4 NFE

AF:

0.267

Gnomad4 OTH

AF:

0.266

Alfa

AF:

0.272

Hom.:

15005

Bravo

AF:

0.292

TwinsUK

AF:

0.291

AC:

1078

ALSPAC

AF:

0.281

AC:

1084

ESP6500AA

AF:

0.263

AC:

1060

ESP6500EA

AF:

0.261

AC:

2191

ExAC

AF:

0.307

AC:

37081

Asia WGS

AF:

0.364

AC:

1267

AN:

3478

EpiCase

AF:

0.256

EpiControl

AF:

0.258

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 12, 2009	- -

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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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

0.066

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.010

T;T;.;.

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.71

T;T;T;T

MetaRNN

Benign

0.00033

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

.;L;.;.

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.46

.;.;.;N

REVEL

Benign

0.071

Sift

Benign

0.34

.;.;.;T

Sift4G

Benign

0.16

T;.;T;T

Polyphen

0.027

.;B;.;.

Vest4

0.044

MPC

0.17

ClinPred

0.026

GERP RS

2.7

Varity_R

0.19

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.49

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.49

Position offset: 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