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with sensorineural hearing loss and one individual with postlingual deafness and bilateral vestibular areflexia (LMM unpublished data SCV000271567.2, ARUP Labs unpublished data SCV000602954.2, University Hospital of Geneva unpublished data SCV000494445.1).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
• nonsyndromic genetic hearing loss

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 1

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022124.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.6866A>G	p.Asn2289Ser	missense	Exon 50 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.146A>G	p.Asn49Ser	missense	Exon 3 of 23	NP_001165404.1	Q9H251-7
	CDH23	NM_001171934.1		c.146A>G	p.Asn49Ser	missense	Exon 3 of 22	NP_001165405.1	Q9H251-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.6866A>G	p.Asn2289Ser	missense	Exon 50 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000475158.1	TSL:1	n.402A>G		non_coding_transcript_exon	Exon 2 of 21
	CDH23	ENST00000642965.1		n.*709A>G		non_coding_transcript_exon	Exon 5 of 25	ENSP00000495222.1	A0A2R8Y6D5

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

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
1	-	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	1	-	Nonsyndromic genetic hearing loss (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.82	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
Polyphen		1.0	D
Vest4		0.90
MutPred		0.65		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;