rs876657756

Variant names:

• chr10-71798390-A-G
• rs876657756
• NM_022124.6:c.6866A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

This summary comes from the ClinGen Evidence Repository: 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with sensorineural hearing loss and one individual with postlingual deafness and bilateral vestibular areflexia (LMM unpublished data SCV000271567.2, ARUP Labs unpublished data SCV000602954.2, University Hospital of Geneva unpublished data SCV000494445.1).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) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10576816/MONDO:0019497/005

• 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
• Publications: 0 publications found

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]

CDH23 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 12

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.6866A>G	p.Asn2289Ser	missense_variant	Exon 50 of 70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171933.1	c.146A>G	p.Asn49Ser	missense_variant	Exon 3 of 23		NP_001165404.1
CDH23	NM_001171934.1	c.146A>G	p.Asn49Ser	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.6866A>G	p.Asn2289Ser	missense_variant	Exon 50 of 70	5	NM_022124.6	ENSP00000224721.9

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111846

Other (OTH) AF: 0.00 AC: 0 AN: 60368

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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

Nov 24, 2023

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 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. -

May 30, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 12 Pathogenic:1

Jun 08, 2016

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 07, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 21, 2022

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

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
MutationAssessor	Uncertain	2.6	.;M;.;.
PhyloP100		9.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.5	.;.;.;D
REVEL	Uncertain	0.53
Sift	Benign	0.032	.;.;.;D
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
Mutation Taster		=17/83	disease causing

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

Other links and lift over

dbSNP: rs876657756; hg19: chr10-73558147;