rs111033457

Positions:

chr10-71813280-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_022124.6(CDH23):c.9670C>T(p.Arg3224Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00107 in 1,551,642 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 5 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:2

Conservation

PhyloP100: 4.70

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:

CDH23 (HGNC:):

CDH23 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12823543).

BP6

Variant 10-71813280-C-T is Benign according to our data. Variant chr10-71813280-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46078.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=8, Benign=1}.

BS2

High Homozygotes in GnomAdExome4 at 5 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6 linkuse as main transcript	c.9670C>T	p.Arg3224Trp	missense_variant	69/70	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.9670C>T	p.Arg3224Trp	missense_variant	69/70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.00102

AC:

155

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00185

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000841

AC:

131

AN:

155776

Hom.:

AF XY:

0.000849

AC XY:

AN XY:

82450

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.000243

Gnomad ASJ exome

AF:

0.000822

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000439

Gnomad FIN exome

AF:

0.00186

Gnomad NFE exome

AF:

0.00141

Gnomad OTH exome

AF:

0.000229

GnomAD4 exome

AF:

0.00107

AC:

1504

AN:

1399348

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

788

AN XY:

690182

show subpopulations

Gnomad4 AFR exome

AF:

0.000158

Gnomad4 AMR exome

AF:

0.000196

Gnomad4 ASJ exome

AF:

0.000755

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000883

Gnomad4 FIN exome

AF:

0.00223

Gnomad4 NFE exome

AF:

0.00122

Gnomad4 OTH exome

AF:

0.000690

GnomAD4 genome

AF:

0.00102

AC:

155

AN:

152294

Hom.:

Cov.:

AF XY:

0.000994

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00185

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.00144

Hom.:

Bravo

AF:

0.000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000456

AC:

ExAC

AF:

0.000384

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 28, 2015	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	Observed in unrelated patients with idiopathic posterior uveitis and POHS in published literature (Li et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32707200) -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	CDH23: PP3 -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 10, 2018	Variant classified as Uncertain Significance - Favor Benign. The p.Arg3224Trp va riant in CDH23 has been identified by our laboratory in 2 individuals with heari ng loss; however, it did not segregate with disease in an affected sibling. This variant has also been identified in 0.18% (132/72638) of European chromosomes, including 1 homozygote, by gnomAD (http://gnomad.broadinstitute.org). This varia nt has also been reported in ClinVar (Variation ID 46078). Computational predict ion tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p. Arg3224Trp variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 26, 2019	- -

CDH23-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Usher syndrome type 1D

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Usher syndrome type 1

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 17, 2020

- -

Autosomal recessive nonsyndromic hearing loss 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.025

T;T;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.063

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Uncertain

0.086

MutationAssessor

Benign

1.0

.;L;.

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.80

.;.;N

REVEL

Uncertain

0.58

Sift

Uncertain

0.0010

.;.;D

Sift4G

Pathogenic

0.0

D;.;D

Polyphen

1.0

.;D;.

Vest4

0.61

MVP

0.92

MPC

0.26

ClinPred

0.066

GERP RS

5.5

Varity_R

0.47

gMVP

0.67

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