chr10-71705068-G-C

Position:

• chr10-71705068-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022124.6(CDH23):​c.2891G>C​(p.Arg964Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R964Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.96

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.2891G>C	p.Arg964Pro	missense_variant	25/70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.2891G>C	p.Arg964Pro	missense_variant	25/32		NP_001165401.1
CDH23	NM_001171931.2	c.2891G>C	p.Arg964Pro	missense_variant	25/26		NP_001165402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.2891G>C	p.Arg964Pro	missense_variant	25/70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 25, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.073	T;T;T;.;T;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T;T;T;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.2	.;.;L;.;.;.
PrimateAI	Uncertain	0.58	T
REVEL	Uncertain	0.50
Sift4G	Uncertain	0.029	D;D;.;D;D;.
Polyphen		0.99	.;.;D;.;.;.
Vest4		0.95
MutPred		0.65		Loss of methylation at R964 (P = 0.0296);Loss of methylation at R964 (P = 0.0296);Loss of methylation at R964 (P = 0.0296);Loss of methylation at R964 (P = 0.0296);Loss of methylation at R964 (P = 0.0296);Loss of methylation at R964 (P = 0.0296);
MVP		0.85
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.72
gMVP		0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs376560330; hg19: chr10-73464825;