rs1057519500

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM3PP3PP4PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_022124.6:c.478G>A variant in the CDH23 gene is a missense variant predicted to cause substitution of aspartic acid to asparagine at amino acid 160 (p.Asp160Asn). The computational predictor REVEL gives a score of 0.8, evidence that correlates with impact to CDH23 function (PP3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0008% (1/112644 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007%) for PM2_Supporting. This variant has been identified in one individual homozygous for the variant with Usher syndrome (PMID:2746042, 0.5 PM3 points, PP4). Another individual with hearing loss and cochlear implants at age 1 year harbored this variant and another pathogenic variant, though phase was unknown (PMID:35020051, 0.5 PM3 points). A third individual with Usher syndrome had a variant of uncertain significance phase unknown (Invitae internal data, SCV001516999.2, 0 PM3 points). It has been reported in additional individuals with hearing loss who either did not have an age of onset noted or did not have a second variant reported (PMID:35020051, 22899989). In summary, due to limited evidence, this variant is classified as a variant of uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Variant Curation Expert Panel: PM2_supporting, PM3, PP3, PP4. (VCEP specifications version 2.0.0; Dec 21, 2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA16044278/MONDO:0019497/005

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:2

Conservation

PhyloP100: 9.56

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 Uncertain_significance. Variant got 5 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6 linkuse as main transcript	c.478G>A	p.Asp160Asn	missense_variant	7/70	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.478G>A	p.Asp160Asn	missense_variant	7/70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248708

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460478

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726262

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 03, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 160 of the CDH23 protein (p.Asp160Asn). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with CDH23-related conditions (PMID: 22899989, 27460420; Invitae). ClinVar contains an entry for this variant (Variation ID: 375463). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CDH23 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Autosomal recessive nonsyndromic hearing loss 12

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center of Genomic medicine, Geneva, University Hospital of Geneva

Jun 08, 2016

This CDH23 heterozygous variant (presumably inherited from the father, but this could not be ascertained) was found in combination with an another CDH23 heterozygous mutation inherited by the mother (see below) in a child with bilateral postlingual deafness and bilateral vestibular areflexia -

Nonsyndromic genetic hearing loss

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Dec 21, 2022

The NM_022124.6:c.478G>A variant in the CDH23 gene is a missense variant predicted to cause substitution of aspartic acid to asparagine at amino acid 160 (p.Asp160Asn). The computational predictor REVEL gives a score of 0.8, evidence that correlates with impact to CDH23 function (PP3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0008% (1/112644 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007%) for PM2_Supporting. This variant has been identified in one individual homozygous for the variant with Usher syndrome (PMID: 2746042, 0.5 PM3 points, PP4). Another individual with hearing loss and cochlear implants at age 1 year harbored this variant and another pathogenic variant, though phase was unknown (PMID: 35020051, 0.5 PM3 points). A third individual with Usher syndrome had a variant of uncertain significance phase unknown (Invitae internal data, SCV001516999.2, 0 PM3 points). It has been reported in additional individuals with hearing loss who either did not have an age of onset noted or did not have a second variant reported (PMID: 35020051, 22899989). In summary, due to limited evidence, this variant is classified as a variant of uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Variant Curation Expert Panel: PM2_supporting, PM3, PP3, PP4. (VCEP specifications version 2.0.0; Dec 21, 2022) -

Usher syndrome type 1

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.25

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

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

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

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.98

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

MetaSVM

Uncertain

0.71

MutationAssessor

Pathogenic

3.7

.;.;H;H;.;.;.;.;.

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-4.4

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

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0020

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.87

MutPred

0.89

Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);.;Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);.;

MVP

0.91

ClinPred

1.0

GERP RS

5.3

Varity_R

0.81

gMVP

0.71

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