rs41281302

Positions:

• chr10-71439831-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022124.6(CDH23):​c.-1C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0333 in 1,560,814 control chromosomes in the GnomAD database, including 2,571 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (1120 hom., cov: 33)
  • Exomes 𝑓: 0.028 (1451 hom.)
• Consequence: CDH23 NM_022124.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.36

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 10-71439831-C-T is Benign according to our data. Variant chr10-71439831-C-T is described in ClinVar as [Benign]. Clinvar id is 162864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71439831-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.-1C>T		5_prime_UTR_variant	2/70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.-1C>T		5_prime_UTR_variant	2/70	5	NM_022124.6	ENSP00000224721	P1

Frequencies

GnomAD3 genomes AF: 0.0791 AC: 12030 AN: 152086 Hom.: 1109 Cov.: 33

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0408

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0540

Gnomad FIN AF: 0.0189

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0235

Gnomad OTH AF: 0.0677

GnomAD3 exomes AF: 0.0367 AC: 6339 AN: 172822 Hom.: 344 AF XY: 0.0347 AC XY: 3189 AN XY: 91872

Gnomad AFR exome AF: 0.218

Gnomad AMR exome AF: 0.0232

Gnomad ASJ exome AF: 0.0355

Gnomad EAS exome AF: 0.000720

Gnomad SAS exome AF: 0.0484

Gnomad FIN exome AF: 0.0202

Gnomad NFE exome AF: 0.0239

Gnomad OTH exome AF: 0.0383

GnomAD4 exome AF: 0.0283 AC: 39816 AN: 1408608 Hom.: 1451 Cov.: 31 AF XY: 0.0284 AC XY: 19766 AN XY: 695958

Gnomad4 AFR exome AF: 0.225

Gnomad4 AMR exome AF: 0.0259

Gnomad4 ASJ exome AF: 0.0353

Gnomad4 EAS exome AF: 0.000189

Gnomad4 SAS exome AF: 0.0484

Gnomad4 FIN exome AF: 0.0226

Gnomad4 NFE exome AF: 0.0213

Gnomad4 OTH exome AF: 0.0382

GnomAD4 genome AF: 0.0794 AC: 12084 AN: 152206 Hom.: 1120 Cov.: 33 AF XY: 0.0771 AC XY: 5736 AN XY: 74422

Gnomad4 AFR AF: 0.219

Gnomad4 AMR AF: 0.0407

Gnomad4 ASJ AF: 0.0334

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0536

Gnomad4 FIN AF: 0.0189

Gnomad4 NFE AF: 0.0235

Gnomad4 OTH AF: 0.0670

Alfa AF: 0.0514 Hom.: 345

Bravo AF: 0.0858

Asia WGS AF: 0.0390 AC: 134 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2018	- -

Usher syndrome type 1D Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Autosomal recessive nonsyndromic hearing loss 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 30, 2010

-1C>T in the 5'UTR of CDH23: This variant is listed in dbSNP with an allele freq uency of 38% in the Black population (rs41281302) and has previously been report ed as non-pathogenic due to identification in control individuals (Astuto 2002). -

Usher syndrome type 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	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: rs41281302; hg19: chr10-73199588;