rs143282422

Positions:

chr10-71617355-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_022124.6(CDH23):c.1096G>A(p.Ala366Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00923 in 1,613,862 control chromosomes in the GnomAD database, including 135 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 0.0065 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0095 ( 128 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:14

Conservation

PhyloP100: 9.24

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008493274).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00653 (994/152264) while in subpopulation NFE AF= 0.00912 (620/68016). AF 95% confidence interval is 0.00852. There are 7 homozygotes in gnomad4. There are 434 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 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.1096G>A	p.Ala366Thr	missense_variant	11/70	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.1096G>A	p.Ala366Thr	missense_variant	11/70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.00653

AC:

994

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00203

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.00543

Gnomad ASJ

AF:

0.0452

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00911

Gnomad OTH

AF:

0.00765

GnomAD3 exomes

AF:

0.00732

AC:

1825

AN:

249204

Hom.:

AF XY:

0.00726

AC XY:

981

AN XY:

135174

show subpopulations

Gnomad AFR exome

AF:

0.00187

Gnomad AMR exome

AF:

0.00452

Gnomad ASJ exome

AF:

0.0487

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00167

Gnomad FIN exome

AF:

0.000979

Gnomad NFE exome

AF:

0.00898

Gnomad OTH exome

AF:

0.0104

GnomAD4 exome

AF:

0.00952

AC:

13910

AN:

1461598

Hom.:

128

Cov.:

AF XY:

0.00943

AC XY:

6857

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.00167

Gnomad4 AMR exome

AF:

0.00517

Gnomad4 ASJ exome

AF:

0.0535

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00210

Gnomad4 FIN exome

AF:

0.00128

Gnomad4 NFE exome

AF:

0.0102

Gnomad4 OTH exome

AF:

0.0104

GnomAD4 genome

AF:

0.00653

AC:

994

AN:

152264

Hom.:

Cov.:

AF XY:

0.00583

AC XY:

434

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00202

Gnomad4 AMR

AF:

0.00542

Gnomad4 ASJ

AF:

0.0452

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00912

Gnomad4 OTH

AF:

0.00757

Alfa

AF:

0.0109

Hom.:

Bravo

AF:

0.00730

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00389

AC:

ESP6500EA

AF:

0.0103

AC:

ExAC

AF:

0.00696

AC:

844

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00965

EpiControl

AF:

0.0107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 13, 2015	- -
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	Jan 30, 2013	Ala366Thr in Exon 11A of CDH23: This variant is not expected to have clinical si gnificance because it has been identified in 1.0% (88/8560) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs143282422). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2018	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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 24, 2020	- -

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 07, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CDH23: BS1, BS2 -

Usher syndrome type 1D

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Autosomal recessive nonsyndromic hearing loss 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 01, 2023

- -

Nonsyndromic genetic hearing loss

Benign:1

Benign, criteria provided, single submitter

clinical testing

INGEBI, INGEBI / CONICET

Jul 15, 2021

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria:The filter allele frequency of c.1096 G>A (A366T) in CDH23 gene is 500/10356 (4,5% with 95% CI) in Ashkenazi Jewish ethnic group in gnomad population database, witch meets the criteria for BA1. Computational evidence is not suffcient to apply to PP3 either BP4 (REVEL:0.198). This variant has been identifiec with c.3293A>G in CDH23 gene in an Usher type 1D patient with unkown phase (PMID:18429043 ). Since c.3293A>G is classified as VUS, PM3 is not applied. Also, A366T was detected in hetercygous state in three usher patients without other variants (PMID: 15660226). Considering BA1, the variant is classified as Benign. -

Usher syndrome type 1

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 15, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0025

T;T;T;.;.;.;T;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0085

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.41

.;.;N;N;.;.;.;.;.

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.98

N;.;N;.;N;.;.;.;.

REVEL

Benign

0.20

Sift

Benign

0.14

T;.;T;.;T;.;.;.;.

Sift4G

Uncertain

0.012

D;D;.;T;D;T;D;.;.

Polyphen

1.0, 1.0

.;.;D;D;.;.;.;.;.

Vest4

0.79

MVP

0.76

ClinPred

0.032

GERP RS

5.2

Varity_R

0.30

gMVP

0.40

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