10-71798371-G-C

Variant names:

• chr10-71798371-G-C
• NM_022124.6:c.6847G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022124.6(CDH23):​c.6847G>C​(p.Val2283Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2283I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.95

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3074082).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.6847G>C	p.Val2283Leu	missense_variant	Exon 50 of 70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171933.1	c.127G>C	p.Val43Leu	missense_variant	Exon 3 of 23		NP_001165404.1
CDH23	NM_001171934.1	c.127G>C	p.Val43Leu	missense_variant	Exon 3 of 22		NP_001165405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.6847G>C	p.Val2283Leu	missense_variant	Exon 50 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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 valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2283 of the CDH23 protein (p.Val2283Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.032	T;T;.;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.5	.;M;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.80	.;.;.;N
REVEL	Benign	0.24
Sift	Benign	0.22	.;.;.;T
Sift4G	Uncertain	0.020	D;.;T;T
Polyphen		0.027	.;B;.;.
Vest4		0.57
MutPred		0.70		Loss of ubiquitination at K2278 (P = 0.1216);Loss of ubiquitination at K2278 (P = 0.1216);.;.;
MVP		0.61
MPC		0.14
ClinPred		0.48	T
GERP RS		3.2
Varity_R		0.099
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-73558128;