rs2394839

Variant names:

• chr10-71784881-A-G
• rs2394839
• NM_022124.6:c.5503-10A>G

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.5503-10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,610,694 control chromosomes in the GnomAD database, including 25,508 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2022 hom., cov: 33)
  • Exomes 𝑓: 0.17 (23486 hom.)
• Consequence: CDH23 NM_022124.6 intron
• Scores: Splicing: ADA: 0.00002974
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.143

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=-0.76).
• BP6: Variant 10-71784881-A-G is Benign according to our data. Variant chr10-71784881-A-G is described in ClinVar as [Benign]. Clinvar id is 45982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71784881-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.5503-10A>G		intron_variant	Intron 42 of 69	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.5503-10A>G		intron_variant	Intron 42 of 69	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22958 AN: 151678 Hom.: 2020 Cov.: 33

Gnomad AFR AF: 0.0693

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.293

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.149

GnomAD3 exomes AF: 0.199 AC: 49640 AN: 248912 Hom.: 5679 AF XY: 0.195 AC XY: 26355 AN XY: 135062

Gnomad AFR exome AF: 0.0687

Gnomad AMR exome AF: 0.337

Gnomad ASJ exome AF: 0.176

Gnomad EAS exome AF: 0.298

Gnomad SAS exome AF: 0.212

Gnomad FIN exome AF: 0.192

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.187

GnomAD4 exome AF: 0.174 AC: 253201 AN: 1458898 Hom.: 23486 Cov.: 32 AF XY: 0.174 AC XY: 126403 AN XY: 725900

Gnomad4 AFR exome AF: 0.0661

Gnomad4 AMR exome AF: 0.325

Gnomad4 ASJ exome AF: 0.177

Gnomad4 EAS exome AF: 0.307

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.188

Gnomad4 NFE exome AF: 0.163

Gnomad4 OTH exome AF: 0.175

GnomAD4 genome AF: 0.151 AC: 22964 AN: 151796 Hom.: 2022 Cov.: 33 AF XY: 0.155 AC XY: 11492 AN XY: 74180

Gnomad4 AFR AF: 0.0692

Gnomad4 AMR AF: 0.215

Gnomad4 ASJ AF: 0.177

Gnomad4 EAS AF: 0.294

Gnomad4 SAS AF: 0.215

Gnomad4 FIN AF: 0.187

Gnomad4 NFE AF: 0.164

Gnomad4 OTH AF: 0.148

Alfa AF: 0.159 Hom.: 3706

Bravo AF: 0.153

Asia WGS AF: 0.240 AC: 834 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Jun 12, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

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 13, 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 13, 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. -

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	-0.76
CADD	Benign	3.1
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.0020
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: rs2394839; hg19: chr10-73544638; COSMIC: COSV56453812;