rs397517354

Positions:

• chr10-71805854-G-A
• chr10-71805854-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_022124.6(CDH23):​c.7921G>A​(p.Asp2641Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.96

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 10-71805854-G-A is Pathogenic according to our data. Variant chr10-71805854-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1072139.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.7921G>A	p.Asp2641Asn	missense_variant	56/70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171933.1	c.1201G>A	p.Asp401Asn	missense_variant	9/23		NP_001165404.1
CDH23	NM_001171934.1	c.1201G>A	p.Asp401Asn	missense_variant	9/22		NP_001165405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.7921G>A	p.Asp2641Asn	missense_variant	56/70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2023

For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt CDH23 protein function. ClinVar contains an entry for this variant (Variation ID: 1072139). This missense change has been observed in individual(s) with type 1 Usher syndrome (PMID: 21940737). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2641 of the CDH23 protein (p.Asp2641Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T;D;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	3.9	.;H;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.0	.;.;.;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	.;.;.;D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.90
MutPred		0.87		Loss of ubiquitination at K2640 (P = 0.0675);Loss of ubiquitination at K2640 (P = 0.0675);.;.;
MVP		0.92
MPC		0.63
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.34
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-73565611;