rs11592462

chr10-71790360-C-G

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.5996C>G(p.Thr1999Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 1,613,008 control chromosomes in the GnomAD database, including 179,488 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. T1999T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.41 (13508 hom., cov: 33)
  • Exomes 𝑓: 0.47 (165980 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.70

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=5.040169E-4).
• BP6: Variant 10-71790360-C-G is Benign according to our data. Variant chr10-71790360-C-G is described in ClinVar as [Benign]. Clinvar id is 45997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71790360-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.5996C>G	p.Thr1999Ser	missense_variant	46/70	ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.5996C>G	p.Thr1999Ser	missense_variant	46/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62191 AN: 151952 Hom.: 13501 Cov.: 33

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.368

Gnomad ASJ AF: 0.529

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.427

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.430

GnomAD3 exomes AF: 0.423 AC: 104457 AN: 246988 Hom.: 23611 AF XY: 0.439 AC XY: 58867 AN XY: 134186

Gnomad AFR exome AF: 0.279

Gnomad AMR exome AF: 0.296

Gnomad ASJ exome AF: 0.527

Gnomad EAS exome AF: 0.165

Gnomad SAS exome AF: 0.519

Gnomad FIN exome AF: 0.422

Gnomad NFE exome AF: 0.487

Gnomad OTH exome AF: 0.445

GnomAD4 exome AF: 0.470 AC: 687244 AN: 1460938 Hom.: 165980 Cov.: 48 AF XY: 0.473 AC XY: 344012 AN XY: 726756

Gnomad4 AFR exome AF: 0.276

Gnomad4 AMR exome AF: 0.302

Gnomad4 ASJ exome AF: 0.524

Gnomad4 EAS exome AF: 0.141

Gnomad4 SAS exome AF: 0.518

Gnomad4 FIN exome AF: 0.428

Gnomad4 NFE exome AF: 0.493

Gnomad4 OTH exome AF: 0.456

GnomAD4 genome AF: 0.409 AC: 62204 AN: 152070 Hom.: 13508 Cov.: 33 AF XY: 0.406 AC XY: 30193 AN XY: 74332

Gnomad4 AFR AF: 0.288

Gnomad4 AMR AF: 0.367

Gnomad4 ASJ AF: 0.529

Gnomad4 EAS AF: 0.165

Gnomad4 SAS AF: 0.512

Gnomad4 FIN AF: 0.427

Gnomad4 NFE AF: 0.494

Gnomad4 OTH AF: 0.434

Alfa AF: 0.474 Hom.: 13287

Bravo AF: 0.392

TwinsUK AF: 0.485 AC: 1800

ALSPAC AF: 0.495 AC: 1907

ESP6500AA AF: 0.270 AC: 1130

ESP6500EA AF: 0.486 AC: 4091

ExAC AF: 0.426 AC: 51511

Asia WGS AF: 0.331 AC: 1154 AN: 3478

EpiCase AF: 0.500

EpiControl AF: 0.499

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Eurofins Ntd Llc (ga)	Oct 28, 2013	- -

Usher syndrome type 1D Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

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	This variant is associated with the following publications: (PMID: 31706157) -

Autosomal recessive nonsyndromic hearing loss 12 Benign:2

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. -
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	0.088
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	18
Dann	Benign	0.97
DEOGEN2	Benign	0.0059	T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.59	T;T
MetaRNN	Benign	0.00050	T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	0.93	P
PrimateAI	Benign	0.41	T
Sift4G	Benign	0.61	T;.
Polyphen		0.0	.;B
Vest4		0.16
MutPred		0.47		Gain of phosphorylation at Y1995 (P = 0.2156);Gain of phosphorylation at Y1995 (P = 0.2156);
ClinPred		0.014	T
GERP RS		4.1
Varity_R		0.099
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs11592462; hg19: chr10-73550117; COSMIC: COSV56463992; COSMIC: COSV56463992;