10-71397276-CCGAGGCGAGG-CCGAGG

Position:

• chr10-71397276-CCGAGGCGAGG-CCGAGG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_022124.6(CDH23):​c.-35_-31del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 172,870 control chromosomes in the GnomAD database, including 1,393 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1313 hom., cov: 0)
  • Exomes 𝑓: 0.067 (80 hom.)
• Consequence: CDH23 NM_022124.6 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.67

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 -16 ACMG points.

• BP6: Variant 10-71397276-CCGAGG-C is Benign according to our data. Variant chr10-71397276-CCGAGG-C is described in ClinVar as [Likely_benign]. Clinvar id is 300395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71397276-CCGAGG-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.-35_-31del		5_prime_UTR_variant	1/70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.-35_-31del		5_prime_UTR_variant	1/70	5	NM_022124.6	ENSP00000224721	P1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16378 AN: 150180 Hom.: 1304 Cov.: 0

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.0437

Gnomad AMR AF: 0.0722

Gnomad ASJ AF: 0.0781

Gnomad EAS AF: 0.0781

Gnomad SAS AF: 0.0968

Gnomad FIN AF: 0.0812

Gnomad MID AF: 0.0955

Gnomad NFE AF: 0.0537

Gnomad OTH AF: 0.104

GnomAD3 exomes AF: 0.0528 AC: 13 AN: 246 Hom.: 0 AF XY: 0.0493 AC XY: 7 AN XY: 142

Gnomad SAS exome AF: 0.00

Gnomad NFE exome AF: 0.0513

Gnomad OTH exome AF: 0.100

GnomAD4 exome AF: 0.0675 AC: 1524 AN: 22584 Hom.: 80 AF XY: 0.0692 AC XY: 986 AN XY: 14252

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.0714

Gnomad4 ASJ exome AF: 0.0652

Gnomad4 EAS exome AF: 0.0833

Gnomad4 SAS exome AF: 0.0917

Gnomad4 FIN exome AF: 0.0754

Gnomad4 NFE exome AF: 0.0508

Gnomad4 OTH exome AF: 0.0602

GnomAD4 genome AF: 0.109 AC: 16417 AN: 150286 Hom.: 1313 Cov.: 0 AF XY: 0.109 AC XY: 7987 AN XY: 73344

Gnomad4 AFR AF: 0.230

Gnomad4 AMR AF: 0.0720

Gnomad4 ASJ AF: 0.0781

Gnomad4 EAS AF: 0.0779

Gnomad4 SAS AF: 0.0957

Gnomad4 FIN AF: 0.0812

Gnomad4 NFE AF: 0.0537

Gnomad4 OTH AF: 0.106

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Outside ROI, common in our data set -
Benign, flagged submission	clinical testing	GeneDx	Nov 12, 2017	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 provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Hearing loss, autosomal recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinitis pigmentosa-deafness syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs71012280; hg19: chr10-73157033;