10-71730508-G-C

Variant names:

• chr10-71730508-G-C
• rs111033488
• NM_022124.6:c.3619G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022124.6(CDH23):​c.3619G>C​(p.Val1207Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 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. V1207M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.11
• 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]

C10orf105 (HGNC:20304): (chromosome 10 open reading frame 105) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29701883).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.3619G>C	p.Val1207Leu	missense_variant	Exon 31 of 70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.3619G>C	p.Val1207Leu	missense_variant	Exon 31 of 32		NP_001165401.1
C10orf105	NM_001168390.2	c.-6+7220C>G		intron_variant	Intron 1 of 1		NP_001161862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.3619G>C	p.Val1207Leu	missense_variant	Exon 31 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T;T;T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.5	.;.;L;.
PhyloP100		4.1
PrimateAI	Benign	0.38	T
REVEL	Benign	0.16
Sift4G	Uncertain	0.034	D;D;.;D
Polyphen		0.076	.;.;B;.
Vest4		0.63
MutPred		0.31		.;Gain of relative solvent accessibility (P = 0.281);Gain of relative solvent accessibility (P = 0.281);Gain of relative solvent accessibility (P = 0.281);
MVP		0.57
ClinPred		0.97	D
GERP RS		4.3
Varity_R		0.16
gMVP		0.22
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs111033488; hg19: chr10-73490265;