rs876657756

chr10-71798390-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_022124.6(CDH23):c.6866A>G(p.Asn2289Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:4
• Conservation: PhyloP100: 9.29

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.6866A>G	p.Asn2289Ser	missense_variant	50/70	ENST00000224721.12
CDH23	NM_001171933.1	c.146A>G	p.Asn49Ser	missense_variant	3/23
CDH23	NM_001171934.1	c.146A>G	p.Asn49Ser	missense_variant	3/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.6866A>G	p.Asn2289Ser	missense_variant	50/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461676 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727128

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 30, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 24, 2023	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 2289 of the CDH23 protein (p.Asn2289Ser). 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: 228500). 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. 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. -

Autosomal recessive nonsyndromic hearing loss 12 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center of Genomic medicine, Geneva, University Hospital of Geneva

Jun 08, 2016

This CDH23 heterozygous variant inherited from the mother was found in combination with an another CDH23 heterozygous mutation (presumably inherited from the father, but this could not be ascertained, see above) in a child with bilateral postlingual deafness and bilateral vestibular areflexia -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 07, 2016

The p.Asn2289Ser variant in CDH23 has not been previously reported in individual s with hearing loss and was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine patho genicity. In summary, the clinical significance of the p.Asn2289Ser variant is u ncertain. -

Nonsyndromic genetic hearing loss Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Dec 21, 2022

The NM_022124.6:c.6866A>G variant in the CDH23 gene is a missense variant predicted to cause substitution of asparagine to serine at amino acid 2289 (p.Asn2289Ser). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.534, which is neither above nor below the thresholds predicting a damaging or benign impact. This variant was reported in two individuals with sensorineural hearing loss and one individual with postlingual deafness and bilateral vestibular areflexia (LMM unpublished data SCV000271567.2, ARUP Labs unpublished data SCV000602954.2, University Hospital of Geneva unpublished data SCV000494445.1). One individual had a second variant of uncertain significance in trans, and one had a second variant of uncertain significance phase unknown (SCV000602954.2, SCV000494445.1) (Does not meet PM3). In summary, due to limited evidence, this variant is classified as a variant of uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Variant Curation Expert Panel: PM2_supporting. (VCEP specifications version 2.0.0; Dec 21, 2022) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;D;.;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Uncertain	0.29	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
Sift4G	Pathogenic	0.0	D;.;T;T
Polyphen		1.0	.;D;.;.
Vest4		0.90
MutPred		0.65		Loss of ubiquitination at K2294 (P = 0.1062);Loss of ubiquitination at K2294 (P = 0.1062);.;.;
MVP		0.88
MPC		0.51
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.52
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs876657756; hg19: chr10-73558147;