10-71397276-CCGAGG-C

Variant names:

• chr10-71397276-CCGAGG-C
• rs71012280
• NM_022124.6:c.-35_-31delAGGCG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_022124.6(CDH23):​c.-35_-31delAGGCG 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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.-35_-31delAGGCG		5_prime_UTR_variant	Exon 1 of 70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721	c.-35_-31delAGGCG		5_prime_UTR_variant	Exon 1 of 70	5	NM_022124.6	ENSP00000224721.9

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

GnomAD2 exomes AF: 0.0528 AC: 13 AN: 246 AF XY: 0.0493

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 AC: 19 AN: 154

Gnomad4 AMR exome AF: 0.0714 AC: 4 AN: 56

Gnomad4 ASJ exome AF: 0.0652 AC: 21 AN: 322

Gnomad4 EAS exome AF: 0.0833 AC: 13 AN: 156

Gnomad4 SAS exome AF: 0.0917 AC: 582 AN: 6350

Gnomad4 FIN exome AF: 0.0754 AC: 96 AN: 1274

Gnomad4 NFE exome AF: 0.0508 AC: 654 AN: 12876

Gnomad4 Remaining exome AF: 0.0602 AC: 53 AN: 880

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 AC: 0.230179 AN: 0.230179

Gnomad4 AMR AF: 0.0720 AC: 0.0720021 AN: 0.0720021

Gnomad4 ASJ AF: 0.0781 AC: 0.078125 AN: 0.078125

Gnomad4 EAS AF: 0.0779 AC: 0.0779327 AN: 0.0779327

Gnomad4 SAS AF: 0.0957 AC: 0.0956649 AN: 0.0956649

Gnomad4 FIN AF: 0.0812 AC: 0.0812207 AN: 0.0812207

Gnomad4 NFE AF: 0.0537 AC: 0.0537302 AN: 0.0537302

Gnomad4 OTH AF: 0.106 AC: 0.106017 AN: 0.106017

Alfa AF: 0.0250 Hom.: 703

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Nov 12, 2017

GeneDx

Significance: Benign

Review Status: flagged submission

Collection Method: clinical testing

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

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hearing loss, autosomal recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa-deafness syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=113/87	polymorphism (auto)

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;