rs397517319

Positions:

• chr10-71707013-G-A
• chr10-71707013-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_022124.6(CDH23):​c.3070G>A​(p.Val1024Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000765 in 1,607,580 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V1024V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000077 (1 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 0.785

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21741995).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.3070G>A	p.Val1024Met	missense_variant	26/70	ENST00000224721.12
CDH23	NM_001171930.2	c.3070G>A	p.Val1024Met	missense_variant	26/32
CDH23	NM_001171931.2	c.3070G>A	p.Val1024Met	missense_variant	26/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.3070G>A	p.Val1024Met	missense_variant	26/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000106 AC: 25 AN: 236402 Hom.: 0 AF XY: 0.000117 AC XY: 15 AN XY: 128432

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000901

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000174

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000122

Gnomad OTH exome AF: 0.000688

GnomAD4 exome AF: 0.0000770 AC: 112 AN: 1455226 Hom.: 1 Cov.: 31 AF XY: 0.0000719 AC XY: 52 AN XY: 723208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000684

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000721

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.0000805 AC XY: 6 AN XY: 74510

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000823 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 20, 2022	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1024 of the CDH23 protein (p.Val1024Met). This variant is present in population databases (rs397517319, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 45907). 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 C15"). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15537665) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2019	- -

CDH23-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 12, 2024

The CDH23 c.3070G>A variant is predicted to result in the amino acid substitution p.Val1024Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.017% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 11, 2014

Val1024Met in exon 26A of CDH23: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, 3 mammals, naked mole rat, Pacific walrus, and elephant, have a methionine (Met) at this position despite high nearby amino acid conservation. In addition , computational prediction tools do not suggest a high likelihood of impact to t he protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T;T;T;.;T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.22	T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.0	.;.;L;.;.;.
MutationTaster	Benign	0.58	D;D
PrimateAI	Uncertain	0.48	T
REVEL	Benign	0.021
Sift4G	Uncertain	0.043	D;D;.;T;T;.
Polyphen		0.010	.;.;B;.;.;.
Vest4		0.11
MVP		0.48
ClinPred		0.045	T
GERP RS		3.4
Varity_R		0.054
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397517319; hg19: chr10-73466770; COSMIC: COSV54928499; COSMIC: COSV54928499;