rs2290021

Positions:

• chr10-71815086-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022124.6(CDH23):​c.9873G>A​(p.Thr3291=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0967 in 1,610,376 control chromosomes in the GnomAD database, including 9,966 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (896 hom., cov: 34)
  • Exomes 𝑓: 0.097 (9070 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -3.53

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-71815086-G-A is Benign according to our data. Variant chr10-71815086-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 46080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71815086-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.273 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.9873G>A	p.Thr3291=	synonymous_variant	70/70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.9873G>A	p.Thr3291=	synonymous_variant	70/70	5	NM_022124.6	ENSP00000224721	P1

Frequencies

GnomAD3 genomes AF: 0.0917 AC: 13958 AN: 152210 Hom.: 894 Cov.: 34

Gnomad AFR AF: 0.0490

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.0570

Gnomad EAS AF: 0.285

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0800

Gnomad OTH AF: 0.0812

GnomAD3 exomes AF: 0.132 AC: 31820 AN: 240552 Hom.: 3165 AF XY: 0.122 AC XY: 16081 AN XY: 131586

Gnomad AFR exome AF: 0.0478

Gnomad AMR exome AF: 0.308

Gnomad ASJ exome AF: 0.0573

Gnomad EAS exome AF: 0.295

Gnomad SAS exome AF: 0.106

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.0780

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.0973 AC: 141839 AN: 1458048 Hom.: 9070 Cov.: 32 AF XY: 0.0957 AC XY: 69422 AN XY: 725224

Gnomad4 AFR exome AF: 0.0448

Gnomad4 AMR exome AF: 0.293

Gnomad4 ASJ exome AF: 0.0576

Gnomad4 EAS exome AF: 0.301

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.129

Gnomad4 NFE exome AF: 0.0829

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.0917 AC: 13962 AN: 152328 Hom.: 896 Cov.: 34 AF XY: 0.0960 AC XY: 7151 AN XY: 74484

Gnomad4 AFR AF: 0.0489

Gnomad4 AMR AF: 0.171

Gnomad4 ASJ AF: 0.0570

Gnomad4 EAS AF: 0.285

Gnomad4 SAS AF: 0.117

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.0800

Gnomad4 OTH AF: 0.0808

Alfa AF: 0.0881 Hom.: 415

Bravo AF: 0.0988

Asia WGS AF: 0.201 AC: 696 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 12, 2009	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 11, 2014	- -

Usher syndrome type 1D Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive nonsyndromic hearing loss 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Atypical Gaucher Disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Combined PSAP deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Usher syndrome type 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Galactosylceramide beta-galactosidase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

- -

Metachromatic leukodystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.22
DANN	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2290021; hg19: chr10-73574843; COSMIC: COSV56446643; COSMIC: COSV56446643;