Genetic Variant CDH23:p.Gly1025Val (chr10-71707017-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_022124.6(CDH23):c.3074G>T(p.Gly1025Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/19 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1025D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.96

Publications

0 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:

ENSG00000300551 (HGNC:):

ENSG00000300551 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.3074G>T	p.Gly1025Val	missense_variant	Exon 26 of 70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152
CDH23	NM_001171930.2 link	c.3074G>T	p.Gly1025Val	missense_variant	Exon 26 of 32		NP_001165401.1	Q9H251A0A087WYR8Q6P152
CDH23	NM_001171931.2 link	c.3074G>T	p.Gly1025Val	missense_variant	Exon 26 of 26		NP_001165402.1	Q9H251Q8N5B3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.3074G>T	p.Gly1025Val	missense_variant	Exon 26 of 70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1455084

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723134

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33400

American (AMR)

AF:

0.00

AC:

AN:

43868

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25992

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39412

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84744

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52682

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109086

Other (OTH)

AF:

0.00

AC:

AN:

60144

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;T;D;.;T;.

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;D;D;D;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D

MetaSVM

Uncertain

0.58

MutationAssessor

Pathogenic

3.2

.;.;M;.;.;.

PhyloP100

PrimateAI

Pathogenic

0.82

REVEL

Pathogenic

0.95

Sift4G

Uncertain

0.0020

D;D;.;D;D;.

Polyphen

1.0

.;.;D;.;.;.

Vest4

0.90

MutPred

0.87

Loss of catalytic residue at D1023 (P = 0.2905);Loss of catalytic residue at D1023 (P = 0.2905);Loss of catalytic residue at D1023 (P = 0.2905);Loss of catalytic residue at D1023 (P = 0.2905);Loss of catalytic residue at D1023 (P = 0.2905);Loss of catalytic residue at D1023 (P = 0.2905);

MVP

0.91

ClinPred

0.99

GERP RS

5.3

Varity_R

0.67

gMVP

0.80

Mutation Taster

=16/84

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over