rs200263980

Positions:

• chr10-71677686-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_022124.6(CDH23):​c.1745G>A​(p.Arg582Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00005 in 1,558,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R582W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 8.14

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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3893303).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.1745G>A	p.Arg582Gln	missense_variant	16/70	ENST00000224721.12
CDH23	NM_001171930.2	c.1745G>A	p.Arg582Gln	missense_variant	16/32
CDH23	NM_001171931.2	c.1745G>A	p.Arg582Gln	missense_variant	16/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.1745G>A	p.Arg582Gln	missense_variant	16/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000303 AC: 5 AN: 165250 Hom.: 0 AF XY: 0.0000228 AC XY: 2 AN XY: 87756

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000396

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000432

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000452

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000505 AC: 71 AN: 1406454 Hom.: 0 Cov.: 31 AF XY: 0.0000590 AC XY: 41 AN XY: 694486

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000551

Gnomad4 SAS exome AF: 0.0000627

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000572

Gnomad4 OTH exome AF: 0.0000342

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74340

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000630 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000240 AC: 2

ExAC AF: 0.00000877 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 23, 2013	The Arg582Gln variant in CDH23 has been reported in 1 Dutch individual with nons yndromic hearing loss; however, a second CDH23 variant was not identified in thi s individual (Astuto 2002). This variant has been identified in 0.02% (2/8324) o f European American chromosomes by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu/EVS/; dbSNP rs200263980). Although this variant has been se en in the general population, its frequency is not high enough to rule out a pat hogenic role. Computational analyses (biochemical amino acid properties, conserv ation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or agai nst an impact to the protein. In summary, additional information is needed to fu lly assess the clinical significance of the Arg582Gln variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 06, 2021	Variant summary: CDH23 c.1745G>A (p.Arg582Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3e-05 in 165250 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1745G>A has been reported in the literature in at least one individual affected with recessive nonsyndromic deafness (Astuto_2002). This report does not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Usher syndrome type 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 19, 2021

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 27, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 582 of the CDH23 protein (p.Arg582Gln). This variant is present in population databases (rs200263980, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of CDH23-related conditions (PMID: 12075507). ClinVar contains an entry for this variant (Variation ID: 177725). 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 not expected to disrupt CDH23 protein function. 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	Benign	0.18
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0043	T;T;T;.;T;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.39	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
Sift4G	Benign	0.12	T;D;.;T;T;.
Polyphen		0.53	.;.;P;.;.;.
Vest4		0.81
MVP		0.79
ClinPred		0.67	D
GERP RS		5.6
Varity_R		0.36
gMVP		0.55

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: rs200263980; hg19: chr10-73437443;