rs142857685

Variant names:

• chr10-71806270-G-A
• rs142857685
• NM_022124.6:c.8167G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71806270-G-A
• chr10-71806270-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022124.6(CDH23):​c.8167G>A​(p.Val2723Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,405,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2723L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.15
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20450908).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.8167G>A	p.Val2723Met	missense_variant	Exon 57 of 70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171933.1	c.1447G>A	p.Val483Met	missense_variant	Exon 10 of 23		NP_001165404.1
CDH23	NM_001171934.1	c.1447G>A	p.Val483Met	missense_variant	Exon 10 of 22		NP_001165405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.8167G>A	p.Val2723Met	missense_variant	Exon 57 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1405802 Hom.: 0 Cov.: 31 AF XY: 0.00000288 AC XY: 2 AN XY: 694502

African (AFR) AF: 0.00 AC: 0 AN: 32030

American (AMR) AF: 0.00 AC: 0 AN: 36792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25282

East Asian (EAS) AF: 0.00 AC: 0 AN: 36412

South Asian (SAS) AF: 0.00 AC: 0 AN: 79744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000277 AC: 3 AN: 1083634

Other (OTH) AF: 0.00 AC: 0 AN: 58408

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.021	T;T;.;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.85	D;D;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	.;L;.;.
PhyloP100		1.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.34	.;.;.;N
REVEL	Benign	0.021
Sift	Benign	0.071	.;.;.;T
Sift4G	Uncertain	0.054	T;.;T;T
Polyphen		0.074	.;B;.;.
Vest4		0.24
MutPred		0.33		Gain of disorder (P = 0.0664);Gain of disorder (P = 0.0664);.;.;
MVP		0.76
MPC		0.15
ClinPred		0.31	T
GERP RS		3.3
Varity_R		0.030
gMVP		0.21
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs142857685; hg19: chr10-73566027; COSMIC: COSV99818879;