rs142131750

Positions:

• chr10-71784932-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_022124.6(CDH23):​c.5544C>T​(p.Asp1848=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,614,084 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0046 (7 hom., cov: 34)
  • Exomes 𝑓: 0.0031 (17 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: 3.17

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 10-71784932-C-T is Benign according to our data. Variant chr10-71784932-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45986.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=4}. Variant chr10-71784932-C-T is described in Lovd as [Benign]. Variant chr10-71784932-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=3.17 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.5544C>T	p.Asp1848=	synonymous_variant	43/70	ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.5544C>T	p.Asp1848=	synonymous_variant	43/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.00462 AC: 704 AN: 152250 Hom.: 7 Cov.: 34

Gnomad AFR AF: 0.00632

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00903

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00425

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00361 AC: 901 AN: 249400 Hom.: 7 AF XY: 0.00350 AC XY: 473 AN XY: 135272

Gnomad AFR exome AF: 0.00682

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.00780

Gnomad NFE exome AF: 0.00392

Gnomad OTH exome AF: 0.00445

GnomAD4 exome AF: 0.00306 AC: 4466 AN: 1461716 Hom.: 17 Cov.: 33 AF XY: 0.00309 AC XY: 2247 AN XY: 727148

Gnomad4 AFR exome AF: 0.00565

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.00383

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00129

Gnomad4 FIN exome AF: 0.00639

Gnomad4 NFE exome AF: 0.00306

Gnomad4 OTH exome AF: 0.00341

GnomAD4 genome AF: 0.00461 AC: 702 AN: 152368 Hom.: 7 Cov.: 34 AF XY: 0.00478 AC XY: 356 AN XY: 74510

Gnomad4 AFR AF: 0.00630

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00903

Gnomad4 NFE AF: 0.00425

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00450 Hom.: 2

Bravo AF: 0.00402

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00267

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CDH23: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 05, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2019	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 30, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 04, 2012	Asp1848Asp in exon 43 of CDH23: This variant is not expected to have clinical si gnificance because it is has been identified in 0.4% (28/6978) of European Ameri can chromosomes and 0.6% (21/3710) of African American chromosomes from a broad population by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/E VS/; dbSNP rs142131750). -

Usher syndrome type 1D Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Usher syndrome type 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 26, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.9
DANN	Benign	0.62

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: rs142131750; hg19: chr10-73544689;