rs1554850744

Variant names:

• chr10-71646541-C-T
• rs1554850744
• NM_022124.6:c.1373C>T

Variant summary

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

The NM_022124.6(CDH23):​c.1373C>T​(p.Pro458Leu) 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88

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, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.1373C>T	p.Pro458Leu	missense_variant	Exon 14 of 70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.1373C>T	p.Pro458Leu	missense_variant	Exon 14 of 32		NP_001165401.1
CDH23	NM_001171931.2	c.1373C>T	p.Pro458Leu	missense_variant	Exon 14 of 26		NP_001165402.1
CDH23	NM_052836.4	c.1373C>T	p.Pro458Leu	missense_variant	Exon 14 of 14		NP_443068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.1373C>T	p.Pro458Leu	missense_variant	Exon 14 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 11, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Pro458Leu variant in CDH23 has not been previously reported in individuals with hearing loss and was absent from large population studies. Computational p rediction tools and conservation analysis suggest that the p.Pro458Leu variant m ay impact the protein, though this information is not predictive enough to deter mine pathogenicity. In summary, the clinical significance of the p.Pro458Leu var iant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;D;.;.;.;T;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	4.4	.;.;H;H;.;.;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-8.4	D;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;.;D;D;D;D;.;.
Polyphen		1.0	.;.;D;D;.;.;.;.;.
Vest4		0.98
MutPred		0.66		Loss of disorder (P = 0.0691);Loss of disorder (P = 0.0691);Loss of disorder (P = 0.0691);Loss of disorder (P = 0.0691);Loss of disorder (P = 0.0691);.;Loss of disorder (P = 0.0691);Loss of disorder (P = 0.0691);.;
MVP		0.93
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.90
gMVP		0.83

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: rs1554850744; hg19: chr10-73406298;