10-71439832-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_022124.6(CDH23):c.1A>T(p.Met1?) variant causes a start lost change. 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 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.16

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.1A>T	p.Met1?	start_lost	2/70	ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.1A>T	p.Met1?	start_lost	2/70	5	NM_022124.6	P1

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 provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 04, 2021

This sequence change affects the initiator methionine of the CDH23 mRNA. The next in-frame methionine is located at codon p.Met60. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CDH23-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts the initiator methionine in CDH23. If translation initiates from the next in-frame methionine, the CDH23 protein would no longer include the region containing the p.Glu44 amino acid residue. Other variant(s) that disrupt this residue have been observed in individuals with CDH23-related conditions (PMID: 30774966), which suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
Cadd	Benign	21
Dann	Benign	0.94
DEOGEN2	Benign	0.0067	T;T;T;.;.;T;.
Eigen	Benign	-0.027
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D
MetaSVM	Benign	-0.66	T
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-0.58	N;.;N;.;N;.;.
REVEL	Uncertain	0.29
Sift	Benign	0.29	T;.;D;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;.
Polyphen		0.17, 0.26	.;.;B;B;.;.;.
Vest4		0.91
MutPred		0.66		Loss of disorder (P = 0.1516);Loss of disorder (P = 0.1516);Loss of disorder (P = 0.1516);Loss of disorder (P = 0.1516);Loss of disorder (P = 0.1516);Loss of disorder (P = 0.1516);Loss of disorder (P = 0.1516);
MVP		0.78
ClinPred		0.97	D
GERP RS		4.6
Varity_R		0.43
gMVP		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-73199589;