10-71695551-T-C

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.2397+26T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.672 in 1,532,188 control chromosomes in the GnomAD database, including 351,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (30278 hom., cov: 35)
  • Exomes 𝑓: 0.68 (320955 hom.)
• Consequence: CDH23 NM_022124.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.83

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=-0.84).
• BP6: Variant 10-71695551-T-C is Benign according to our data. Variant chr10-71695551-T-C is described in ClinVar as [Benign]. Clinvar id is 261545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71695551-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.706 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.2397+26T>C		intron_variant		ENST00000224721.12
CDH23	NM_001171930.2	c.2397+26T>C		intron_variant
CDH23	NM_001171931.2	c.2397+26T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.2397+26T>C		intron_variant		5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.625 AC: 95011 AN: 152046 Hom.: 30270 Cov.: 35

Gnomad AFR AF: 0.528

Gnomad AMI AF: 0.657

Gnomad AMR AF: 0.564

Gnomad ASJ AF: 0.781

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.618

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.711

Gnomad OTH AF: 0.654

GnomAD3 exomes AF: 0.628 AC: 155281 AN: 247240 Hom.: 50124 AF XY: 0.640 AC XY: 85924 AN XY: 134152

Gnomad AFR exome AF: 0.520

Gnomad AMR exome AF: 0.467

Gnomad ASJ exome AF: 0.764

Gnomad EAS exome AF: 0.501

Gnomad SAS exome AF: 0.630

Gnomad FIN exome AF: 0.558

Gnomad NFE exome AF: 0.711

Gnomad OTH exome AF: 0.656

GnomAD4 exome AF: 0.678 AC: 934982 AN: 1380024 Hom.: 320955 Cov.: 22 AF XY: 0.679 AC XY: 469048 AN XY: 690952

Gnomad4 AFR exome AF: 0.507

Gnomad4 AMR exome AF: 0.475

Gnomad4 ASJ exome AF: 0.770

Gnomad4 EAS exome AF: 0.476

Gnomad4 SAS exome AF: 0.633

Gnomad4 FIN exome AF: 0.566

Gnomad4 NFE exome AF: 0.707

Gnomad4 OTH exome AF: 0.665

GnomAD4 genome AF: 0.625 AC: 95050 AN: 152164 Hom.: 30278 Cov.: 35 AF XY: 0.617 AC XY: 45904 AN XY: 74392

Gnomad4 AFR AF: 0.528

Gnomad4 AMR AF: 0.563

Gnomad4 ASJ AF: 0.781

Gnomad4 EAS AF: 0.476

Gnomad4 SAS AF: 0.618

Gnomad4 FIN AF: 0.553

Gnomad4 NFE AF: 0.711

Gnomad4 OTH AF: 0.650

Alfa AF: 0.683 Hom.: 7284

Bravo AF: 0.622

Asia WGS AF: 0.522 AC: 1818 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

not provided Benign:1

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. -

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	-0.84
Cadd	Benign	0.053
Dann	Benign	0.23

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: rs3752750; hg19: chr10-73455308;