rs763721044

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

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 Conflicting classifications of pathogenicity (no stars).

Frequency

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

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 9.96

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 12
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Usher syndrome type 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 1D
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CDH23 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_022124.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.946

PP5

Variant 10-71805836-G-T is Pathogenic according to our data. Variant chr10-71805836-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228503.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CDH23	NM_022124.6 link	c.7903G>T	p.Val2635Phe	missense_variant	Exon 56 of 70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171933.1 link	c.1183G>T	p.Val395Phe	missense_variant	Exon 9 of 23		NP_001165404.1
CDH23	NM_001171934.1 link	c.1183G>T	p.Val395Phe	missense_variant	Exon 9 of 22		NP_001165405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.7903G>T	p.Val2635Phe	missense_variant	Exon 56 of 70	5	NM_022124.6	ENSP00000224721.9

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

GnomAD2 exomes

AF:

0.0000282

AC:

AN:

248118

AF XY:

0.0000297

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 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

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.000134

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111812

Other (OTH)

AF:

0.0000166

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.000196

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000197

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types

Pathogenic:1

Mar 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hearing loss, autosomal recessive

Pathogenic:1

May 01, 2024

Laboratory of Human Genetics, Universidade de São Paulo

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The CDH23:NM_022124.5:c.7903G>T variant has extremely low frequency in gnomAD population databases (PM2), reported in ClinVar in affected individuals (PP5), Cosegregation with disease in two affected family members in a gene definitively known to cause the disease (PP1), computational prediction tools unanimously support a deleterious effect on the gene (PP3). Here it was found in trans with c.3820G>A in two affected siblings, born from unaffected unrelated couple. -

Autosomal recessive nonsyndromic hearing loss 12

Pathogenic:1

Feb 19, 2016

Laboratory of Prof. Karen Avraham, Tel Aviv University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Congenital, profound HL -

not specified

Uncertain:1

Dec 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

May 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

MutationAssessor

Uncertain

2.6

.;M;.;.

PhyloP100

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.0

.;D;.;D

REVEL

Uncertain

0.59

Sift

Uncertain

0.0010

.;D;.;D

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

Mutation Taster

=8/92

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over