chr10-71646691-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_052836.4(CDH23):c.1523G>T(p.Cys508Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,613,648 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C508Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0082 ( 23 hom., cov: 33)

Exomes 𝑓: 0.00093 ( 22 hom. )

Consequence

CDH23
NM_052836.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0780

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=0.002867937).

BP6

Variant 10-71646691-G-T is Benign according to our data. Variant chr10-71646691-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 46543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71646691-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00818 (1246/152286) while in subpopulation AFR AF= 0.0287 (1194/41538). AF 95% confidence interval is 0.0274. There are 23 homozygotes in gnomad4. There are 574 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 23 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.1449+74G>T		intron_variant	Intron 14 of 69	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152
CDH23	NM_052836.4 link	c.1523G>T	p.Cys508Phe	missense_variant	Exon 14 of 14		NP_443068.1	Q9H251-5
CDH23	NM_001171930.2 link	c.1449+74G>T		intron_variant	Intron 14 of 31		NP_001165401.1	Q9H251A0A087WYR8Q6P152
CDH23	NM_001171931.2 link	c.1449+74G>T		intron_variant	Intron 14 of 25		NP_001165402.1	Q9H251Q8N5B3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.1449+74G>T		intron_variant	Intron 14 of 69	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.00817

AC:

1243

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0288

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00221

AC:

546

AN:

247558

Hom.:

AF XY:

0.00176

AC XY:

237

AN XY:

134426

show subpopulations

Gnomad AFR exome

AF:

0.0311

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.000398

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000117

Gnomad OTH exome

AF:

0.000828

GnomAD4 exome

AF:

0.000929

AC:

1357

AN:

1461362

Hom.:

Cov.:

AF XY:

0.000776

AC XY:

564

AN XY:

726894

show subpopulations

Gnomad4 AFR exome

AF:

0.0313

Gnomad4 AMR exome

AF:

0.00134

Gnomad4 ASJ exome

AF:

0.000918

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000756

Gnomad4 OTH exome

AF:

0.00209

GnomAD4 genome

AF:

0.00818

AC:

1246

AN:

152286

Hom.:

Cov.:

AF XY:

0.00771

AC XY:

574

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0287

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00427

Hom.:

Bravo

AF:

0.00943

ESP6500AA

AF:

0.0260

AC:

103

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00270

AC:

326

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Cys508Phe in Exon 14 of CDH23: This variant is not expected to have clinical sig nificance because it has been identified in 2.7% (88/3278) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs115450602). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CDH23-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.50

CADD

Benign

3.9

DANN

Benign

0.94

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.34

T;T

MetaRNN

Benign

0.0029

T;T

MetaSVM

Benign

-1.0

REVEL

Benign

0.081

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.90

P;.

Vest4

0.18

MVP

0.39

ClinPred

0.0074

GERP RS

2.3

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