rs41281302

Variant names:

• chr10-71439831-C-T
• rs41281302
• NM_022124.6:c.-1C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 publications found

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]

CDH23 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 12

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.
• 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 rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.-1C>T		5_prime_UTR_variant	Exon 2 of 70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.-1C>T		5_prime_UTR_variant	Exon 2 of 70	5	NM_022124.6	ENSP00000224721.9

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

GnomAD2 exomes AF: 0.0367 AC: 6339 AN: 172822 AF XY: 0.0347

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 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

African (AFR) AF: 0.225 AC: 7157 AN: 31832

American (AMR) AF: 0.0259 AC: 966 AN: 37274

Ashkenazi Jewish (ASJ) AF: 0.0353 AC: 892 AN: 25286

East Asian (EAS) AF: 0.000189 AC: 7 AN: 36980

South Asian (SAS) AF: 0.0484 AC: 3864 AN: 79908

European-Finnish (FIN) AF: 0.0226 AC: 1134 AN: 50190

Middle Eastern (MID) AF: 0.0813 AC: 462 AN: 5686

European-Non Finnish (NFE) AF: 0.0213 AC: 23103 AN: 1083104

Other (OTH) AF: 0.0382 AC: 2231 AN: 58348

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

African (AFR) AF: 0.219 AC: 9093 AN: 41478

American (AMR) AF: 0.0407 AC: 623 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0334 AC: 116 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5182

South Asian (SAS) AF: 0.0536 AC: 259 AN: 4830

European-Finnish (FIN) AF: 0.0189 AC: 201 AN: 10624

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0235 AC: 1599 AN: 68004

Other (OTH) AF: 0.0670 AC: 141 AN: 2106

Alfa AF: 0.0539 Hom.: 405

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

Nov 12, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1D Benign:2

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Autosomal recessive nonsyndromic hearing loss 12 Benign:2

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

Nov 30, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

-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

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.83
PhyloP100		1.4
PromoterAI		-0.046	Neutral
Mutation Taster		=275/25	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41281302; hg19: chr10-73199588;