rs3802711

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022124.6(CDH23):c.5411G>A(p.Arg1804Gln) variant causes a missense change. The variant allele was found at a frequency of 0.169 in 1,613,564 control chromosomes in the GnomAD database, including 24,289 homozygotes. In-silico tool predicts 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. R1804W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.14 ( 1707 hom., cov: 33)

Exomes 𝑓: 0.17 ( 22582 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.57

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=0.0017862618).

BP6

Variant 10-71784329-G-A is Benign according to our data. Variant chr10-71784329-G-A is described in ClinVar as [Benign]. Clinvar id is 45978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71784329-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6 linkuse as main transcript	c.5411G>A	p.Arg1804Gln	missense_variant	42/70	ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.5411G>A	p.Arg1804Gln	missense_variant	42/70	5	NM_022124.6	P1	Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.142

AC:

21573

AN:

152092

Hom.:

1708

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0746

Gnomad AMI

AF:

0.138

Gnomad AMR

AF:

0.130

Gnomad ASJ

AF:

0.124

Gnomad EAS

AF:

0.247

Gnomad SAS

AF:

0.108

Gnomad FIN

AF:

0.213

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.170

Gnomad OTH

AF:

0.138

GnomAD3 exomes

AF:

0.155

AC:

38608

AN:

249008

Hom.:

3310

AF XY:

0.154

AC XY:

20809

AN XY:

135108

show subpopulations

Gnomad AFR exome

AF:

0.0714

Gnomad AMR exome

AF:

0.107

Gnomad ASJ exome

AF:

0.124

Gnomad EAS exome

AF:

0.237

Gnomad SAS exome

AF:

0.106

Gnomad FIN exome

AF:

0.211

Gnomad NFE exome

AF:

0.174

Gnomad OTH exome

AF:

0.145

GnomAD4 exome

AF:

0.172

AC:

251202

AN:

1461354

Hom.:

22582

Cov.:

AF XY:

0.170

AC XY:

123285

AN XY:

726992

show subpopulations

Gnomad4 AFR exome

AF:

0.0721

Gnomad4 AMR exome

AF:

0.109

Gnomad4 ASJ exome

AF:

0.126

Gnomad4 EAS exome

AF:

0.272

Gnomad4 SAS exome

AF:

0.106

Gnomad4 FIN exome

AF:

0.208

Gnomad4 NFE exome

AF:

0.179

Gnomad4 OTH exome

AF:

0.162

GnomAD4 genome

AF:

0.142

AC:

21576

AN:

152210

Hom.:

1707

Cov.:

AF XY:

0.143

AC XY:

10655

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0745

Gnomad4 AMR

AF:

0.130

Gnomad4 ASJ

AF:

0.124

Gnomad4 EAS

AF:

0.247

Gnomad4 SAS

AF:

0.108

Gnomad4 FIN

AF:

0.213

Gnomad4 NFE

AF:

0.170

Gnomad4 OTH

AF:

0.136

Alfa

AF:

0.165

Hom.:

3614

Bravo

AF:

0.134

TwinsUK

AF:

0.182

AC:

675

ALSPAC

AF:

0.174

AC:

670

ESP6500AA

AF:

0.0779

AC:

310

ESP6500EA

AF:

0.164

AC:

1367

ExAC

AF:

0.154

AC:

18664

Asia WGS

AF:

0.129

AC:

448

AN:

3478

EpiCase

AF:

0.164

EpiControl

AF:

0.167

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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	GeneDx	Jan 07, 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	PreventionGenetics, part of Exact Sciences	-	- -

Usher syndrome type 1D

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Autosomal recessive nonsyndromic hearing loss 12

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Usher syndrome type 1

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Retinitis pigmentosa-deafness syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.24

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.014

T;T

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-1.2

MutationTaster

Benign

0.0000079

PrimateAI

Uncertain

0.53

Sift4G

Uncertain

0.0070

D;.

Polyphen

1.0

.;D

Vest4

0.50

ClinPred

0.0074

GERP RS

5.4

Varity_R

0.57

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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