chr10-71679448-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_022124.6(CDH23):c.1814C>T(p.Ala605Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000573 in 1,613,550 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00040 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00059 ( 5 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:7

Conservation

PhyloP100: 1.48

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010247946).

BP6

Variant 10-71679448-C-T is Benign according to our data. Variant chr10-71679448-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45883.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=1, Uncertain_significance=4}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0004 (61/152384) while in subpopulation SAS AF= 0.00331 (16/4828). AF 95% confidence interval is 0.00208. There are 1 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.1814C>T	p.Ala605Val	missense_variant	Exon 17 of 70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152
CDH23	NM_001171930.2 link	c.1814C>T	p.Ala605Val	missense_variant	Exon 17 of 32		NP_001165401.1	Q9H251A0A087WYR8Q6P152
CDH23	NM_001171931.2 link	c.1814C>T	p.Ala605Val	missense_variant	Exon 17 of 26		NP_001165402.1	Q9H251Q8N5B3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.1814C>T	p.Ala605Val	missense_variant	Exon 17 of 70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00107

AC:

266

AN:

247572

Hom.:

AF XY:

0.00118

AC XY:

159

AN XY:

134468

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.00146

Gnomad ASJ exome

AF:

0.00379

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00441

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000286

Gnomad OTH exome

AF:

0.00166

GnomAD4 exome

AF:

0.000591

AC:

864

AN:

1461166

Hom.:

Cov.:

AF XY:

0.000724

AC XY:

526

AN XY:

726814

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00150

Gnomad4 ASJ exome

AF:

0.00360

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00431

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000209

Gnomad4 OTH exome

AF:

0.000878

GnomAD4 genome

AF:

0.000400

AC:

AN:

152384

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74520

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00518

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00331

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000528

Hom.:

Bravo

AF:

0.000416

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000251

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.000993

AC:

120

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Oct 02, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1D

Uncertain:1Benign:1

May 18, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified

Benign:2

Jun 16, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala605Val in exon 17 of CDH23: This variant is not expected to have clinical s ignificance because it has been identified in 0.4% (53/13978) of South Asian chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs201475055). In addition the alanine (Ala) at position 605 is not co nserved across species with chinchilla and panda have this variant (Val) at this position despite high nearby amino acid conservation. -

Jul 27, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CDH23-related disorder

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome

Uncertain:1

Dec 31, 2022

SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Autosomal recessive nonsyndromic hearing loss 12

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Usher syndrome type 1

Benign:1

Apr 15, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.015

T;T;T;.;T;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.83

T;T;T;T;T;T

M_CAP

Benign

0.0052

MetaRNN

Benign

0.010

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.59

.;.;N;.;.;.

PrimateAI

Uncertain

0.53

REVEL

Benign

0.073

Sift4G

Benign

0.15

T;T;.;T;T;.

Polyphen

0.0010

.;.;B;.;.;.

Vest4

0.32

MVP

0.66

ClinPred

0.016

GERP RS

4.0

Varity_R

0.098

gMVP

0.28

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