rs56181447

chr10-71738598-G-Achr10-71738598-G-C

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.4310G>A(p.Arg1437Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0305 in 1,613,762 control chromosomes in the GnomAD database, including 1,255 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1437K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.038 (159 hom., cov: 33)
  • Exomes 𝑓: 0.030 (1096 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 1.45

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=0.0017529726).
• BP6: Variant 10-71738598-G-A is Benign according to our data. Variant chr10-71738598-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 45944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71738598-G-A is described in Lovd as [Benign]. Variant chr10-71738598-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0794 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.4310G>A	p.Arg1437Gln	missense_variant	35/70	ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.4310G>A	p.Arg1437Gln	missense_variant	35/70	5	NM_022124.6	P1
CDH23	ENST00000398792.3	n.999G>A		non_coding_transcript_exon_variant	6/9	2

Frequencies

GnomAD3 genomes AF: 0.0378 AC: 5753 AN: 152220 Hom.: 157 Cov.: 33

Gnomad AFR AF: 0.0569

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0298

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.0860

Gnomad SAS AF: 0.0467

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0255

Gnomad OTH AF: 0.0397

GnomAD3 exomes AF: 0.0361 AC: 8985 AN: 249066 Hom.: 280 AF XY: 0.0375 AC XY: 5072 AN XY: 135170

Gnomad AFR exome AF: 0.0552

Gnomad AMR exome AF: 0.0184

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.0875

Gnomad SAS exome AF: 0.0486

Gnomad FIN exome AF: 0.00367

Gnomad NFE exome AF: 0.0273

Gnomad OTH exome AF: 0.0334

GnomAD4 exome AF: 0.0297 AC: 43378 AN: 1461424 Hom.: 1096 Cov.: 32 AF XY: 0.0306 AC XY: 22270 AN XY: 726988

Gnomad4 AFR exome AF: 0.0540

Gnomad4 AMR exome AF: 0.0193

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.105

Gnomad4 SAS exome AF: 0.0481

Gnomad4 FIN exome AF: 0.00497

Gnomad4 NFE exome AF: 0.0240

Gnomad4 OTH exome AF: 0.0363

GnomAD4 genome AF: 0.0379 AC: 5767 AN: 152338 Hom.: 159 Cov.: 33 AF XY: 0.0369 AC XY: 2751 AN XY: 74492

Gnomad4 AFR AF: 0.0572

Gnomad4 AMR AF: 0.0297

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.0860

Gnomad4 SAS AF: 0.0468

Gnomad4 FIN AF: 0.00395

Gnomad4 NFE AF: 0.0255

Gnomad4 OTH AF: 0.0393

Alfa AF: 0.0324 Hom.: 147

Bravo AF: 0.0418

TwinsUK AF: 0.0248 AC: 92

ALSPAC AF: 0.0252 AC: 97

ESP6500AA AF: 0.0487 AC: 203

ESP6500EA AF: 0.0287 AC: 243

ExAC AF: 0.0371 AC: 4488

Asia WGS AF: 0.0630 AC: 220 AN: 3478

EpiCase AF: 0.0333

EpiControl AF: 0.0354

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	GeneDx	Feb 14, 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. -

not provided Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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	Genome-Nilou Lab	Jul 01, 2021	- -
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. -

Autosomal recessive nonsyndromic hearing loss 12 Benign:2

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

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	0.084
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0079	T;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.62	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.12	P;P
PrimateAI	Benign	0.24	T
Sift4G	Uncertain	0.019	D;.
Polyphen		0.13	.;B
Vest4		0.31
ClinPred		0.0097	T
GERP RS		1.5
Varity_R		0.24
gMVP		0.41

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: rs56181447; hg19: chr10-73498355; COSMIC: COSV56455366; COSMIC: COSV56455366;