10-71784847-T-C

Variant names:

• chr10-71784847-T-C
• rs7068810
• NM_022124.6:c.5503-44T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022124.6(CDH23):​c.5503-44T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 1,528,944 control chromosomes in the GnomAD database, including 28,434 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3220 hom., cov: 33)
  • Exomes 𝑓: 0.19 (25214 hom.)
• Consequence: CDH23 NM_022124.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.66
• Publications: 6 publications found

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]

CDH23 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 12

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 10-71784847-T-C is Benign according to our data. Variant chr10-71784847-T-C is described in ClinVar as Benign. ClinVar VariationId is 261552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.5503-44T>C		intron_variant	Intron 42 of 69	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.5503-44T>C		intron_variant	Intron 42 of 69	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30718 AN: 152042 Hom.: 3217 Cov.: 33

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.196

GnomAD2 exomes AF: 0.181 AC: 44377 AN: 245768 AF XY: 0.177

Gnomad AFR exome AF: 0.261

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.238

Gnomad FIN exome AF: 0.213

Gnomad NFE exome AF: 0.188

Gnomad OTH exome AF: 0.164

GnomAD4 exome AF: 0.188 AC: 259323 AN: 1376784 Hom.: 25214 Cov.: 22 AF XY: 0.186 AC XY: 127884 AN XY: 689394

African (AFR) AF: 0.259 AC: 8210 AN: 31752

American (AMR) AF: 0.127 AC: 5618 AN: 44408

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 4120 AN: 25618

East Asian (EAS) AF: 0.272 AC: 10698 AN: 39268

South Asian (SAS) AF: 0.131 AC: 11073 AN: 84466

European-Finnish (FIN) AF: 0.211 AC: 11224 AN: 53178

Middle Eastern (MID) AF: 0.132 AC: 743 AN: 5642

European-Non Finnish (NFE) AF: 0.190 AC: 196943 AN: 1034908

Other (OTH) AF: 0.186 AC: 10694 AN: 57544

GnomAD4 genome AF: 0.202 AC: 30738 AN: 152160 Hom.: 3220 Cov.: 33 AF XY: 0.201 AC XY: 14961 AN XY: 74390

African (AFR) AF: 0.254 AC: 10535 AN: 41520

American (AMR) AF: 0.161 AC: 2455 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 563 AN: 3468

East Asian (EAS) AF: 0.249 AC: 1284 AN: 5166

South Asian (SAS) AF: 0.129 AC: 619 AN: 4814

European-Finnish (FIN) AF: 0.218 AC: 2310 AN: 10602

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.182 AC: 12402 AN: 67984

Other (OTH) AF: 0.194 AC: 410 AN: 2110

Alfa AF: 0.190 Hom.: 11501

Bravo AF: 0.201

Asia WGS AF: 0.151 AC: 526 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1D Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 12 Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.2
DANN	Benign	0.38
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7068810; hg19: chr10-73544604; COSMIC: COSV56452789;