rs3802708

Positions:

• chr10-71799470-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.7225-22C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0857 in 1,613,664 control chromosomes in the GnomAD database, including 8,777 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (839 hom., cov: 33)
  • Exomes 𝑓: 0.086 (7938 hom.)
• Consequence: CDH23 NM_022124.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0380

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=-0.62).
• BP6: Variant 10-71799470-C-T is Benign according to our data. Variant chr10-71799470-C-T is described in ClinVar as [Benign]. Clinvar id is 261554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71799470-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.7225-22C>T		intron_variant		ENST00000224721.12	NP_071407.4
CDH23	NM_001171933.1	c.505-22C>T		intron_variant			NP_001165404.1
CDH23	NM_001171934.1	c.505-22C>T		intron_variant			NP_001165405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.7225-22C>T		intron_variant		5	NM_022124.6	ENSP00000224721	P1

Frequencies

GnomAD3 genomes AF: 0.0842 AC: 12820 AN: 152204 Hom.: 837 Cov.: 33

Gnomad AFR AF: 0.0475

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.0516

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0655

Gnomad OTH AF: 0.0759

GnomAD3 exomes AF: 0.123 AC: 30730 AN: 249172 Hom.: 3152 AF XY: 0.114 AC XY: 15404 AN XY: 135170

Gnomad AFR exome AF: 0.0468

Gnomad AMR exome AF: 0.300

Gnomad ASJ exome AF: 0.0523

Gnomad EAS exome AF: 0.299

Gnomad SAS exome AF: 0.107

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.0632

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.0859 AC: 125536 AN: 1461342 Hom.: 7938 Cov.: 33 AF XY: 0.0848 AC XY: 61628 AN XY: 726974

Gnomad4 AFR exome AF: 0.0451

Gnomad4 AMR exome AF: 0.286

Gnomad4 ASJ exome AF: 0.0524

Gnomad4 EAS exome AF: 0.310

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.124

Gnomad4 NFE exome AF: 0.0687

Gnomad4 OTH exome AF: 0.0918

GnomAD4 genome AF: 0.0842 AC: 12828 AN: 152322 Hom.: 839 Cov.: 33 AF XY: 0.0889 AC XY: 6619 AN XY: 74486

Gnomad4 AFR AF: 0.0474

Gnomad4 AMR AF: 0.164

Gnomad4 ASJ AF: 0.0516

Gnomad4 EAS AF: 0.290

Gnomad4 SAS AF: 0.120

Gnomad4 FIN AF: 0.123

Gnomad4 NFE AF: 0.0655

Gnomad4 OTH AF: 0.0761

Alfa AF: 0.0693 Hom.: 85

Bravo AF: 0.0912

Asia WGS AF: 0.208 AC: 722 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Usher syndrome type 1D Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Autosomal recessive nonsyndromic hearing loss 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.9
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3802708; hg19: chr10-73559227; COSMIC: COSV56453712;