10-71793565-G-C

Variant names:

• chr10-71793565-G-C
• rs375900265
• NM_022124.6:c.6637G>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.6637G>C​(p.Gly2213Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 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. G2213S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.13
• Publications: 1 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=0.20858404).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.6637G>C	p.Gly2213Arg	missense	Exon 48 of 70	NP_071407.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.6637G>C	p.Gly2213Arg	missense	Exon 48 of 70	ENSP00000224721.9
	CDH23	ENST00000642965.1		n.-72G>C		upstream_gene	N/A	ENSP00000495222.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.1
PrimateAI	Benign	0.30	T
REVEL	Benign	0.094
Sift4G	Benign	0.081	T
Polyphen		0.19	B
Vest4		0.48
MutPred		0.70		Loss of ubiquitination at K2217 (P = 0.1139)
MVP		0.80
ClinPred		0.25	T
GERP RS		-0.76
Varity_R		0.14
gMVP		0.50
Mutation Taster		=91/9	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: rs375900265; hg19: chr10-73553322;