10-71730595-C-T

Position:

• chr10-71730595-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_022124.6(CDH23):​c.3706C>T​(p.Arg1236Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CDH23 NM_022124.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.54

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

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 10-71730595-C-T is Pathogenic according to our data. Variant chr10-71730595-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 45929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71730595-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.3706C>T	p.Arg1236Ter	stop_gained	31/70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.3706C>T	p.Arg1236Ter	stop_gained	31/32		NP_001165401.1
C10orf105	NM_001168390.2	c.-6+7133G>A		intron_variant			NP_001161862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.3706C>T	p.Arg1236Ter	stop_gained	31/70	5	NM_022124.6	ENSP00000224721	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248664 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135072

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461502 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727044

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2015	The R1236X nonsense variant in the CDH23 gene is predicted to cause loss of normal protein functioneither through protein truncation or nonsense-mediated mRNA decay. The R1236X variant was notobserved in approximately 6,200 individuals of European and African American ancestry in the NHLBIExome Sequencing Project, indicating it is not a common benign variant in these populations. Although thisvariant has not been reported previously to our knowledge, we consider it to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 09, 2023	This sequence change creates a premature translational stop signal (p.Arg1236*) in the CDH23 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDH23 are known to be pathogenic (PMID: 11138009, 21940737). This variant is present in population databases (rs397517327, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 45929). For these reasons, this variant has been classified as Pathogenic. -

Pituitary adenoma 5, multiple types Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 29, 2023

- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 29, 2012

The Arg1236X variant in CDH23 has not been reported in the literature nor previo usly identified by our laboratory. This nonsense variant leads to a premature te rmination codon at position 1236, which is predicted to lead to a truncated or a bsent protein. In summary, this variant meets our criteria to be classified as p athogenic (http://pcpgm.partners.org/LMM). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.80	D
MutationTaster	Benign	1.0	D;A;A
Vest4		0.96
GERP RS		1.1

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: rs397517327; hg19: chr10-73490352; COSMIC: COSV56466829;