10-71778352-C-G

Variant names:

• chr10-71778352-C-G
• rs10740390
• NM_022124.6:c.5187+44C>G

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.5187+44C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 1,608,898 control chromosomes in the GnomAD database, including 122,477 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13310 hom., cov: 32)
  • Exomes 𝑓: 0.38 (109167 hom.)
• Consequence: CDH23 NM_022124.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.211
• Publications: 9 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

ENSG00000306531 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-71778352-C-G is Benign according to our data. Variant chr10-71778352-C-G is described in ClinVar as Benign. ClinVar VariationId is 261551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.481 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.5187+44C>G		intron_variant	Intron 40 of 69	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.5187+44C>G		intron_variant	Intron 40 of 69	5	NM_022124.6	ENSP00000224721.9
ENSG00000306531	ENST00000819235.1	n.158-1287G>C		intron_variant	Intron 1 of 1
ENSG00000306531	ENST00000819236.1	n.157-1184G>C		intron_variant	Intron 1 of 1
ENSG00000306531	ENST00000819237.1	n.146-1282G>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62875 AN: 151882 Hom.: 13291 Cov.: 32

Gnomad AFR AF: 0.487

Gnomad AMI AF: 0.412

Gnomad AMR AF: 0.399

Gnomad ASJ AF: 0.366

Gnomad EAS AF: 0.489

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.435

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.372

Gnomad OTH AF: 0.383

GnomAD2 exomes AF: 0.406 AC: 98939 AN: 243630 AF XY: 0.396

Gnomad AFR exome AF: 0.496

Gnomad AMR exome AF: 0.476

Gnomad ASJ exome AF: 0.363

Gnomad EAS exome AF: 0.485

Gnomad FIN exome AF: 0.435

Gnomad NFE exome AF: 0.373

Gnomad OTH exome AF: 0.379

GnomAD4 exome AF: 0.384 AC: 560138 AN: 1456898 Hom.: 109167 Cov.: 34 AF XY: 0.382 AC XY: 276874 AN XY: 724310

African (AFR) AF: 0.498 AC: 16610 AN: 33342

American (AMR) AF: 0.466 AC: 20612 AN: 44208

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 9559 AN: 26038

East Asian (EAS) AF: 0.523 AC: 20712 AN: 39584

South Asian (SAS) AF: 0.357 AC: 30660 AN: 85974

European-Finnish (FIN) AF: 0.427 AC: 22670 AN: 53126

Middle Eastern (MID) AF: 0.289 AC: 1655 AN: 5720

European-Non Finnish (NFE) AF: 0.374 AC: 414340 AN: 1108730

Other (OTH) AF: 0.388 AC: 23320 AN: 60176

GnomAD4 genome AF: 0.414 AC: 62943 AN: 152000 Hom.: 13310 Cov.: 32 AF XY: 0.414 AC XY: 30784 AN XY: 74302

African (AFR) AF: 0.487 AC: 20187 AN: 41454

American (AMR) AF: 0.399 AC: 6098 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 1268 AN: 3468

East Asian (EAS) AF: 0.489 AC: 2524 AN: 5162

South Asian (SAS) AF: 0.360 AC: 1733 AN: 4820

European-Finnish (FIN) AF: 0.435 AC: 4593 AN: 10548

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.372 AC: 25288 AN: 67944

Other (OTH) AF: 0.380 AC: 803 AN: 2112

Alfa AF: 0.308 Hom.: 1243

Bravo AF: 0.417

Asia WGS AF: 0.407 AC: 1416 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

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	-0.83
CADD	Benign	7.1
DANN	Benign	0.74
PhyloP100		0.21
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: rs10740390; hg19: chr10-73538109; COSMIC: COSV56478978; COSMIC: COSV56478978;