rs200649500

Variant names:

• chr10-71694209-C-G
• rs200649500
• NM_022124.6:c.2239C>G

Your query was ambiguous. Multiple possible variants found:

• chr10-71694209-C-G
• chr10-71694209-C-T

Variant summary

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

The NM_022124.6(CDH23):​c.2239C>G​(p.Arg747Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R747C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.28
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.2239C>G	p.Arg747Gly	missense_variant	Exon 21 of 70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.2239C>G	p.Arg747Gly	missense_variant	Exon 21 of 32		NP_001165401.1
CDH23	NM_001171931.2	c.2239C>G	p.Arg747Gly	missense_variant	Exon 21 of 26		NP_001165402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.2239C>G	p.Arg747Gly	missense_variant	Exon 21 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	T;T;T;.;T;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Uncertain	0.095	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.5	.;.;L;.;.;.
PhyloP100		3.3
PrimateAI	Uncertain	0.66	T
REVEL	Uncertain	0.35
Sift4G	Benign	0.067	T;D;.;D;T;.
Polyphen		0.88	.;.;P;.;.;.
Vest4		0.95
MutPred		0.63		Loss of stability (P = 0.0273);Loss of stability (P = 0.0273);Loss of stability (P = 0.0273);Loss of stability (P = 0.0273);Loss of stability (P = 0.0273);Loss of stability (P = 0.0273);
MVP		0.66
ClinPred		0.90	D
GERP RS		4.6
Varity_R		0.64
gMVP		0.81
Mutation Taster		=52/48	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: rs200649500; hg19: chr10-73453966; COSMIC: COSV106386325;