rs7902757

chr10-71439838-C-T

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.7C>T(p.Arg3Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0403 in 1,563,838 control chromosomes in the GnomAD database, including 5,378 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.12 (2655 hom., cov: 33)
  • Exomes 𝑓: 0.032 (2723 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.134

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=0.00406006).
• BP6: Variant 10-71439838-C-T is Benign according to our data. Variant chr10-71439838-C-T is described in ClinVar as [Benign]. Clinvar id is 46042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71439838-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.7C>T	p.Arg3Cys	missense_variant	2/70	ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.7C>T	p.Arg3Cys	missense_variant	2/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17618 AN: 151998 Hom.: 2644 Cov.: 33

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0567

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0549

Gnomad FIN AF: 0.0194

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0240

Gnomad OTH AF: 0.0945

GnomAD3 exomes AF: 0.0455 AC: 8039 AN: 176796 Hom.: 734 AF XY: 0.0417 AC XY: 3928 AN XY: 94102

Gnomad AFR exome AF: 0.348

Gnomad AMR exome AF: 0.0306

Gnomad ASJ exome AF: 0.0356

Gnomad EAS exome AF: 0.00101

Gnomad SAS exome AF: 0.0486

Gnomad FIN exome AF: 0.0210

Gnomad NFE exome AF: 0.0242

Gnomad OTH exome AF: 0.0427

GnomAD4 exome AF: 0.0321 AC: 45367 AN: 1411720 Hom.: 2723 Cov.: 31 AF XY: 0.0317 AC XY: 22140 AN XY: 697690

Gnomad4 AFR exome AF: 0.353

Gnomad4 AMR exome AF: 0.0336

Gnomad4 ASJ exome AF: 0.0354

Gnomad4 EAS exome AF: 0.000269

Gnomad4 SAS exome AF: 0.0490

Gnomad4 FIN exome AF: 0.0230

Gnomad4 NFE exome AF: 0.0217

Gnomad4 OTH exome AF: 0.0475

GnomAD4 genome AF: 0.116 AC: 17676 AN: 152118 Hom.: 2655 Cov.: 33 AF XY: 0.113 AC XY: 8383 AN XY: 74376

Gnomad4 AFR AF: 0.346

Gnomad4 AMR AF: 0.0567

Gnomad4 ASJ AF: 0.0334

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0543

Gnomad4 FIN AF: 0.0194

Gnomad4 NFE AF: 0.0240

Gnomad4 OTH AF: 0.0935

Alfa AF: 0.0411 Hom.: 847

Bravo AF: 0.128

TwinsUK AF: 0.0235 AC: 87

ALSPAC AF: 0.0223 AC: 86

ESP6500AA AF: 0.326 AC: 1330

ESP6500EA AF: 0.0242 AC: 202

ExAC AF: 0.0389 AC: 4607

Asia WGS AF: 0.0470 AC: 165 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -

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	- -

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	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 02, 2009

- -

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	0.087
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	16
Dann	Benign	0.94
DEOGEN2	Benign	0.021	T;T;T;.;.;T;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.73	T;T;T;T;T;T;T
MetaRNN	Benign	0.0041	T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.99	P;P;P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.060	N;.;N;.;N;.;.
REVEL	Benign	0.077
Sift	Benign	0.068	T;.;T;.;T;.;.
Sift4G	Benign	0.20	T;T;T;T;T;T;.
Polyphen		0.0	.;.;B;B;.;.;.
Vest4		0.061
ClinPred		0.013	T
GERP RS		0.54
Varity_R		0.089
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs7902757; hg19: chr10-73199595; COSMIC: COSV54932823;