rs41281334

chr10-71798371-G-Achr10-71798371-G-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.6847G>A(p.Val2283Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0457 in 1,613,470 control chromosomes in the GnomAD database, including 2,222 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. V2283L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.038 (165 hom., cov: 32)
  • Exomes 𝑓: 0.046 (2057 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 3.95

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=0.0013784468).
• BP6: Variant 10-71798371-G-A is Benign according to our data. Variant chr10-71798371-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 46019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71798371-G-A is described in Lovd as [Benign]. Variant chr10-71798371-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.6847G>A	p.Val2283Ile	missense_variant	50/70	ENST00000224721.12
CDH23	NM_001171933.1	c.127G>A	p.Val43Ile	missense_variant	3/23
CDH23	NM_001171934.1	c.127G>A	p.Val43Ile	missense_variant	3/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.6847G>A	p.Val2283Ile	missense_variant	50/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5859 AN: 152140 Hom.: 164 Cov.: 32

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.0937

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.0433

Gnomad SAS AF: 0.0255

Gnomad FIN AF: 0.0335

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0453

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0554 AC: 13802 AN: 249244 Hom.: 747 AF XY: 0.0504 AC XY: 6810 AN XY: 135224

Gnomad AFR exome AF: 0.00929

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.0486

Gnomad SAS exome AF: 0.0273

Gnomad FIN exome AF: 0.0366

Gnomad NFE exome AF: 0.0412

Gnomad OTH exome AF: 0.0562

GnomAD4 exome AF: 0.0465 AC: 67919 AN: 1461212 Hom.: 2057 Cov.: 32 AF XY: 0.0451 AC XY: 32779 AN XY: 726942

Gnomad4 AFR exome AF: 0.00851

Gnomad4 AMR exome AF: 0.165

Gnomad4 ASJ exome AF: 0.0107

Gnomad4 EAS exome AF: 0.0339

Gnomad4 SAS exome AF: 0.0276

Gnomad4 FIN exome AF: 0.0393

Gnomad4 NFE exome AF: 0.0465

Gnomad4 OTH exome AF: 0.0409

GnomAD4 genome AF: 0.0385 AC: 5860 AN: 152258 Hom.: 165 Cov.: 32 AF XY: 0.0385 AC XY: 2864 AN XY: 74452

Gnomad4 AFR AF: 0.0104

Gnomad4 AMR AF: 0.0939

Gnomad4 ASJ AF: 0.00979

Gnomad4 EAS AF: 0.0434

Gnomad4 SAS AF: 0.0251

Gnomad4 FIN AF: 0.0335

Gnomad4 NFE AF: 0.0453

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0402 Hom.: 274

Bravo AF: 0.0450

TwinsUK AF: 0.0526 AC: 195

ALSPAC AF: 0.0516 AC: 199

ESP6500AA AF: 0.0102 AC: 44

ESP6500EA AF: 0.0459 AC: 391

ExAC AF: 0.0493 AC: 5979

Asia WGS AF: 0.0360 AC: 126 AN: 3478

EpiCase AF: 0.0405

EpiControl AF: 0.0399

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 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	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
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)	Jul 01, 2015	- -

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

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	- -

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	0.054
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	8.2
Dann	Benign	0.27
DEOGEN2	Benign	0.010	T;T;.;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.73	T;T;T;T
MetaRNN	Benign	0.0014	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.51	D;D
PrimateAI	Benign	0.26	T
Sift4G	Benign	0.70	T;.;T;T
Polyphen		0.014	.;B;.;.
Vest4		0.077
MPC		0.12
ClinPred		0.0024	T
GERP RS		3.2
Varity_R		0.036
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41281334; hg19: chr10-73558128;