rs115113440

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6

The NM_022124.6(CDH23):c.5753G>A(p.Arg1918Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000318 in 1,608,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1918W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 0.567

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 Likely_benign. Variant got -3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_022124.6

BP4

Computational evidence support a benign effect (MetaRNN=0.0065231025).

BP6

Variant 10-71785671-G-A is Benign according to our data. Variant chr10-71785671-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45992.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=1, Benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6 linkuse as main transcript	c.5753G>A	p.Arg1918Gln	missense_variant	44/70	ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.5753G>A	p.Arg1918Gln	missense_variant	44/70	5	NM_022124.6	P1	Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.00160

AC:

243

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00533

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000410

AC:

AN:

238958

Hom.:

AF XY:

0.000317

AC XY:

AN XY:

129480

show subpopulations

Gnomad AFR exome

AF:

0.00567

Gnomad AMR exome

AF:

0.000356

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000347

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000461

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.000183

AC:

267

AN:

1455770

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

122

AN XY:

723442

show subpopulations

Gnomad4 AFR exome

AF:

0.00609

Gnomad4 AMR exome

AF:

0.000317

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000709

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.000316

GnomAD4 genome

AF:

0.00160

AC:

244

AN:

152312

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

110

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00534

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000329

Hom.:

Bravo

AF:

0.00171

ESP6500AA

AF:

0.00427

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000562

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

CDH23-related disorder

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 18, 2022	The CDH23 c.5753G>A variant is predicted to result in the amino acid substitution p.Arg1918Gln. This variant was reported in a patient with hearing loss, although conclusive evidence of pathogenicity was not presented (Table S3, Sloan-Heggen et al 2016. PubMed ID: 26969326). This variant is reported in 0.55% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-73545428-G-A), which is higher than expected for a pathogenic variant in this gene. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 16, 2010	Arg1918Gln in exon 44 of CDH23: This variant is not predicted to have clinical s ignificance because the Arg1918 residue is not conserved across species and is r eplaced with the variant Gln residue in Chicken. Furthermore, computational anal yses predict that the variant will not affect the protein. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 08, 2014	- -

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 16, 2020

- -

Autosomal recessive nonsyndromic hearing loss 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.58

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.010

T;T

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.60

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.0065

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.53

PrimateAI

Benign

0.22

Sift4G

Benign

0.21

T;.

Polyphen

0.073

.;B

Vest4

0.40

MVP

0.58

ClinPred

0.013

GERP RS

2.3

Varity_R

0.072

gMVP

0.36

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