rs3802720

Positions:

• chr10-71511149-T-C
• chr10-71511149-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022124.6(CDH23):​c.366T>C​(p.Val122=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.67 in 1,613,518 control chromosomes in the GnomAD database, including 367,376 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (42372 hom., cov: 32)
  • Exomes 𝑓: 0.66 (325004 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.73

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-AS1 (HGNC:31433): (CDH23 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 10-71511149-T-C is Benign according to our data. Variant chr10-71511149-T-C is described in ClinVar as [Benign]. Clinvar id is 45928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71511149-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.73 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.922 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.366T>C	p.Val122=	synonymous_variant	6/70	ENST00000224721.12
CDH23-AS1	NR_120672.1	n.143+629A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.366T>C	p.Val122=	synonymous_variant	6/70	5	NM_022124.6	P1
CDH23-AS1	ENST00000428918.1	n.96+629A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.734 AC: 111543 AN: 151966 Hom.: 42323 Cov.: 32

Gnomad AFR AF: 0.930

Gnomad AMI AF: 0.495

Gnomad AMR AF: 0.579

Gnomad ASJ AF: 0.735

Gnomad EAS AF: 0.777

Gnomad SAS AF: 0.597

Gnomad FIN AF: 0.747

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.659

Gnomad OTH AF: 0.700

GnomAD3 exomes AF: 0.661 AC: 164866 AN: 249270 Hom.: 56414 AF XY: 0.660 AC XY: 89254 AN XY: 135230

Gnomad AFR exome AF: 0.940

Gnomad AMR exome AF: 0.458

Gnomad ASJ exome AF: 0.733

Gnomad EAS exome AF: 0.778

Gnomad SAS exome AF: 0.601

Gnomad FIN exome AF: 0.733

Gnomad NFE exome AF: 0.663

Gnomad OTH exome AF: 0.660

GnomAD4 exome AF: 0.664 AC: 969722 AN: 1461434 Hom.: 325004 Cov.: 56 AF XY: 0.662 AC XY: 481285 AN XY: 727026

Gnomad4 AFR exome AF: 0.944

Gnomad4 AMR exome AF: 0.469

Gnomad4 ASJ exome AF: 0.728

Gnomad4 EAS exome AF: 0.758

Gnomad4 SAS exome AF: 0.607

Gnomad4 FIN exome AF: 0.726

Gnomad4 NFE exome AF: 0.658

Gnomad4 OTH exome AF: 0.683

GnomAD4 genome AF: 0.734 AC: 111644 AN: 152084 Hom.: 42372 Cov.: 32 AF XY: 0.734 AC XY: 54512 AN XY: 74308

Gnomad4 AFR AF: 0.930

Gnomad4 AMR AF: 0.578

Gnomad4 ASJ AF: 0.735

Gnomad4 EAS AF: 0.777

Gnomad4 SAS AF: 0.597

Gnomad4 FIN AF: 0.747

Gnomad4 NFE AF: 0.659

Gnomad4 OTH AF: 0.697

Alfa AF: 0.674 Hom.: 43337

Bravo AF: 0.727

Asia WGS AF: 0.684 AC: 2379 AN: 3478

EpiCase AF: 0.655

EpiControl AF: 0.654

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2012	Inferred frequency = 136/301 -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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	- -

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	-0.85
CADD	Benign	0.18
DANN	Benign	0.65

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: rs3802720; hg19: chr10-73270906; COSMIC: COSV54944416; COSMIC: COSV54944416;