10-71397124-T-TGCGAGCG

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_022124.6(CDH23):c.-176_-170dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 175,626 control chromosomes in the GnomAD database, including 68 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.017 (68 hom., cov: 30)
  • Exomes 𝑓: 0.00061 (0 hom.)
• Consequence: CDH23 NM_022124.6 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.-176_-170dup		5_prime_UTR_variant	1/70	ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.-176_-170dup		5_prime_UTR_variant	1/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2547 AN: 147714 Hom.: 68 Cov.: 30

Gnomad AFR AF: 0.0573

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00795

Gnomad ASJ AF: 0.00350

Gnomad EAS AF: 0.000631

Gnomad SAS AF: 0.000663

Gnomad FIN AF: 0.0000991

Gnomad MID AF: 0.0145

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.0141

GnomAD4 exome AF: 0.000612 AC: 17 AN: 27782 Hom.: 0 Cov.: 0 AF XY: 0.000824 AC XY: 15 AN XY: 18196

Gnomad4 AFR exome AF: 0.0179

Gnomad4 AMR exome AF: 0.0149

Gnomad4 ASJ exome AF: 0.00292

Gnomad4 EAS exome AF: 0.00292

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000384

Gnomad4 OTH exome AF: 0.00293

GnomAD4 genome AF: 0.0173 AC: 2554 AN: 147844 Hom.: 68 Cov.: 30 AF XY: 0.0164 AC XY: 1184 AN XY: 72204

Gnomad4 AFR AF: 0.0573

Gnomad4 AMR AF: 0.00794

Gnomad4 ASJ AF: 0.00350

Gnomad4 EAS AF: 0.000633

Gnomad4 SAS AF: 0.000663

Gnomad4 FIN AF: 0.0000991

Gnomad4 NFE AF: 0.00123

Gnomad4 OTH AF: 0.0140

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

CDH23-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Nonsyndromic Hearing Loss, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinitis pigmentosa-deafness syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 18, 2021

- -

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: rs527578984; hg19: chr10-73156881;