rs10999947

chr10-71675149-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022124.6(CDH23):c.1487G>A(p.Ser496Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,612,966 control chromosomes in the GnomAD database, including 60,315 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5568 hom., cov: 32)
  • Exomes 𝑓: 0.27 (54747 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.420

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006324768).
• BP6: Variant 10-71675149-G-A is Benign according to our data. Variant chr10-71675149-G-A is described in ClinVar as [Benign]. Clinvar id is 45875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71675149-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.1487G>A	p.Ser496Asn	missense_variant	15/70	ENST00000224721.12
CDH23	NM_001171930.2	c.1487G>A	p.Ser496Asn	missense_variant	15/32
CDH23	NM_001171931.2	c.1487G>A	p.Ser496Asn	missense_variant	15/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.1487G>A	p.Ser496Asn	missense_variant	15/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.270 AC: 41019 AN: 152038 Hom.: 5559 Cov.: 32

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.273

GnomAD3 exomes AF: 0.274 AC: 68122 AN: 249022 Hom.: 9483 AF XY: 0.272 AC XY: 36716 AN XY: 135132

Gnomad AFR exome AF: 0.255

Gnomad AMR exome AF: 0.306

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.297

Gnomad SAS exome AF: 0.270

Gnomad FIN exome AF: 0.301

Gnomad NFE exome AF: 0.266

Gnomad OTH exome AF: 0.264

GnomAD4 exome AF: 0.272 AC: 396639 AN: 1460810 Hom.: 54747 Cov.: 34 AF XY: 0.271 AC XY: 196966 AN XY: 726734

Gnomad4 AFR exome AF: 0.258

Gnomad4 AMR exome AF: 0.304

Gnomad4 ASJ exome AF: 0.186

Gnomad4 EAS exome AF: 0.244

Gnomad4 SAS exome AF: 0.272

Gnomad4 FIN exome AF: 0.306

Gnomad4 NFE exome AF: 0.272

Gnomad4 OTH exome AF: 0.274

GnomAD4 genome AF: 0.270 AC: 41072 AN: 152156 Hom.: 5568 Cov.: 32 AF XY: 0.272 AC XY: 20224 AN XY: 74396

Gnomad4 AFR AF: 0.257

Gnomad4 AMR AF: 0.296

Gnomad4 ASJ AF: 0.187

Gnomad4 EAS AF: 0.269

Gnomad4 SAS AF: 0.260

Gnomad4 FIN AF: 0.310

Gnomad4 NFE AF: 0.271

Gnomad4 OTH AF: 0.276

Alfa AF: 0.266 Hom.: 13579

Bravo AF: 0.268

TwinsUK AF: 0.256 AC: 950

ALSPAC AF: 0.282 AC: 1088

ESP6500AA AF: 0.230 AC: 963

ESP6500EA AF: 0.260 AC: 2193

ExAC AF: 0.272 AC: 32861

Asia WGS AF: 0.261 AC: 907 AN: 3478

EpiCase AF: 0.258

EpiControl AF: 0.256

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 09, 2009	- -

Usher syndrome type 1D Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Autosomal recessive nonsyndromic hearing loss 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Usher syndrome type 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.70
Dann	Benign	0.44
DEOGEN2	Benign	0.011	T;T;T;.;T;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.064	T;T;T;T;T;T
MetaRNN	Benign	0.0063	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.33	T
Sift4G	Benign	0.65	T;T;.;T;T;.
Polyphen		0.0	.;.;B;.;.;.
Vest4		0.056
ClinPred		0.0030	T
GERP RS		-0.61
Varity_R		0.047
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs10999947; hg19: chr10-73434906; COSMIC: COSV99819113;