rs763721044

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_022124.6(CDH23):c.7903G>T(p.Val2635Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 9.96

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 Uncertain_significance. Variant got 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CDH23	NM_022124.6 linkuse as main transcript	c.7903G>T	p.Val2635Phe	missense_variant	56/70	ENST00000224721.12
CDH23	NM_001171933.1 linkuse as main transcript	c.1183G>T	p.Val395Phe	missense_variant	9/23
CDH23	NM_001171934.1 linkuse as main transcript	c.1183G>T	p.Val395Phe	missense_variant	9/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.7903G>T	p.Val2635Phe	missense_variant	56/70	5	NM_022124.6	P1	Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000282

AC:

AN:

248118

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

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:

0.00000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461458

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726986

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 12

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory of Prof. Karen Avraham, Tel Aviv University

Feb 19, 2016

Congenital, profound HL -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 24, 2014

The p.Val2635Phe variant in CDH23 has been previously reported in 3 Jewish-Alger ian individuals with hearing loss (Brownstein 2011, Idan 2013). The variant was identified in the homozygous state in two of these individuals and was present i n the heterozygous state in the third individual who did not carry a second CDH2 3 variant on the other allele. The variant apparently segregated with the hearin g loss in affected family members in two pedigrees; however one family was consa nguineous (which increases the presence of homozygous variants in offspring irre spective of their clinical significance) and, although consanguinity was not rep orted for the second family, all affected family members, including two affected apparently unrelated spouses, were homozygous for the variant. The variant was not identified in 106 ethnically-matched controls; however, this sample size is too small to accurately determine the population frequency of the variant. Given that the variant has only been seen in the homozygous state and was not observe d in compound heterozygosity with a known CDH23 pathogenic variant in affected i ndividuals, as well as the fact that these families all have a unique shared anc estry with limited control data, the information in these studies does not provi de sufficient evidence to assume that the p.Val2635Phe variant is causative for hearing loss. The p.Val2635Phe variant has also been identified in 4/10962 of La tino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org), but this frequency is not high enough to rule out a pathogenic role . Computational prediction tools and conservation analysis suggest that this var iant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, due to insufficient data to support pathog enicity, and the limited evidence and control data presented in the studies abov e, the clinical significance of the p.Val2635Phe variant in CDH23 is uncertain. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 27, 2022

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2635 of the CDH23 protein (p.Val2635Phe). This variant is present in population databases (rs763721044, gnomAD 0.01%). This missense change has been observed in individual(s) with deafness (PMID: 19888295, 21917145). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 228503). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.23

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.083

T;T;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Uncertain

-0.12

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.67

Sift4G

Uncertain

0.0020

D;.;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.94

MutPred

0.86

Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;.;

MVP

0.90

MPC

0.72

ClinPred

0.98

GERP RS

5.9

Varity_R

0.67

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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