rs397517352

chr10-71802916-G-Achr10-71802916-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022124.6(CDH23):c.7501G>A(p.Asp2501Asn) 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D2501D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.47

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.7501G>A	p.Asp2501Asn	missense_variant	54/70	ENST00000224721.12
CDH23	NM_001171933.1	c.781G>A	p.Asp261Asn	missense_variant	7/23
CDH23	NM_001171934.1	c.781G>A	p.Asp261Asn	missense_variant	7/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.7501G>A	p.Asp2501Asn	missense_variant	54/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 18, 2012

The Asp2501Asn variant in CDH23 has not been reported in the literature nor prev iously identified by our laboratory. Computational analyses (biochemical amino a cid properties, conservation, PolyPhen2, SIFT, AlignGVGD) do not provide strong support for or against pathogenicity. In summary, the clinical significance of t his variant cannot be determined with certainty at this time. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 02, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 46033). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. 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 2501 of the CDH23 protein (p.Asp2501Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;D;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.98
MutPred		0.69		Loss of stability (P = 0.2059);Loss of stability (P = 0.2059);.;.;
MVP		0.90
MPC		0.61
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.60
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs397517352; hg19: chr10-73562673;