rs201297042

Positions:

• chr10-71677536-C-A
• chr10-71677536-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_022124.6(CDH23):​c.1595C>A​(p.Thr532Lys) 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. 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. T532M) 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: 7.83

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain Cadherin 5 (size 100) in uniprot entity CAD23_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_022124.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.1595C>A	p.Thr532Lys	missense_variant	16/70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.1595C>A	p.Thr532Lys	missense_variant	16/32		NP_001165401.1
CDH23	NM_001171931.2	c.1595C>A	p.Thr532Lys	missense_variant	16/26		NP_001165402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.1595C>A	p.Thr532Lys	missense_variant	16/70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.065	T;T;T;.;T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.4	.;.;L;.;.;.
PrimateAI	Uncertain	0.70	T
REVEL	Uncertain	0.40
Sift4G	Uncertain	0.045	D;D;.;T;D;.
Polyphen		0.66	.;.;P;.;.;.
Vest4		0.87
MutPred		0.66		Gain of ubiquitination at T532 (P = 0.0211);Gain of ubiquitination at T532 (P = 0.0211);Gain of ubiquitination at T532 (P = 0.0211);Gain of ubiquitination at T532 (P = 0.0211);Gain of ubiquitination at T532 (P = 0.0211);Gain of ubiquitination at T532 (P = 0.0211);
MVP		0.79
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.31
gMVP		0.77

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: rs201297042; hg19: chr10-73437293;