10-71807381-C-G

Variant names:

• chr10-71807381-C-G
• rs397517357
• NM_022124.6:c.8283C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022124.6(CDH23):​c.8283C>G​(p.Asn2761Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,562 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -3.12

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.8283C>G	p.Asn2761Lys	missense_variant	Exon 58 of 70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171933.1	c.1563C>G	p.Asn521Lys	missense_variant	Exon 11 of 23		NP_001165404.1
CDH23	NM_001171934.1	c.1563C>G	p.Asn521Lys	missense_variant	Exon 11 of 22		NP_001165405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.8283C>G	p.Asn2761Lys	missense_variant	Exon 58 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461562 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727064

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Aug 19, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Asn2761Lys variant in the CDH23 gene has not been reported in the literature nor previously identified by our laboratory. The Asn (Asparagine) residue is co nserved across mammals and chicken and computational analyses (PolyPhen, SIFT, A lignGVGD) suggest that the Lys (Lysine) variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. It should be noted that this lab has only sequenced the CDH23 gene in 121 individuals such t hat the full spectrum of benign variation has not yet been defined for this gene . Therefore, it is possible that this could be a benign variant. In summary, the clinical significance of this variant cannot be determined with certainty at th is time. -

Usher syndrome type 1 Uncertain:1

Feb 21, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1

Aug 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 2761 of the CDH23 protein (p.Asn2761Lys). This variant is not present in population databases (gnomAD no frequency). 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: 46047). 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 C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	2.6
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;.;.
Eigen	Benign	-0.040
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Uncertain	-0.089	T
MutationAssessor	Uncertain	2.8	.;M;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.9	.;.;.;N
REVEL	Uncertain	0.45
Sift	Uncertain	0.028	.;.;.;D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		0.99	.;D;.;.
Vest4		0.87
MutPred		0.71		Gain of methylation at N2761 (P = 0.0012);Gain of methylation at N2761 (P = 0.0012);.;.;
MVP		0.72
MPC		0.68
ClinPred		0.84	D
GERP RS		-3.8
Varity_R		0.84
gMVP		0.80

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

LitVar

Other links and lift over

dbSNP: rs397517357; hg19: chr10-73567138;