chr10-71707013-G-T

Position:

• chr10-71707013-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022124.6(CDH23):​c.3070G>T​(p.Val1024Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.785

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34699172).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.3070G>T	p.Val1024Leu	missense_variant	26/70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.3070G>T	p.Val1024Leu	missense_variant	26/32		NP_001165401.1
CDH23	NM_001171931.2	c.3070G>T	p.Val1024Leu	missense_variant	26/26		NP_001165402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.3070G>T	p.Val1024Leu	missense_variant	26/70	5	NM_022124.6	ENSP00000224721	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455226 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 723208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0078	T;T;T;.;T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.35	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.12	.;.;N;.;.;.
MutationTaster	Benign	0.55	D;D
PrimateAI	Benign	0.45	T
REVEL	Benign	0.015
Sift4G	Benign	0.29	T;T;.;T;T;.
Polyphen		0.0040	.;.;B;.;.;.
Vest4		0.23
MutPred		0.40		Loss of catalytic residue at V1024 (P = 0.074);Loss of catalytic residue at V1024 (P = 0.074);Loss of catalytic residue at V1024 (P = 0.074);Loss of catalytic residue at V1024 (P = 0.074);Loss of catalytic residue at V1024 (P = 0.074);Loss of catalytic residue at V1024 (P = 0.074);
MVP		0.46
ClinPred		0.83	D
GERP RS		3.4
Varity_R		0.070
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397517319; hg19: chr10-73466770;