rs111033458

Positions:

• chr10-71705055-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_022124.6(CDH23):​c.2878G>A​(p.Glu960Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00368 in 1,612,632 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (17 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 2.73

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010432005).
• BP6: Variant 10-71705055-G-A is Benign according to our data. Variant chr10-71705055-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45904.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=7}. Variant chr10-71705055-G-A is described in Lovd as [Benign]. Variant chr10-71705055-G-A is described in Lovd as [Likely_benign]. Variant chr10-71705055-G-A is described in Lovd as [Likely_pathogenic].
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.2878G>A	p.Glu960Lys	missense_variant	25/70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.2878G>A	p.Glu960Lys	missense_variant	25/32		NP_001165401.1
CDH23	NM_001171931.2	c.2878G>A	p.Glu960Lys	missense_variant	25/26		NP_001165402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.2878G>A	p.Glu960Lys	missense_variant	25/70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 447 AN: 152186 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00469

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00302 AC: 742 AN: 245864 Hom.: 5 AF XY: 0.00306 AC XY: 412 AN XY: 134448

Gnomad AFR exome AF: 0.000597

Gnomad AMR exome AF: 0.00369

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.0000560

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00135

Gnomad NFE exome AF: 0.00499

Gnomad OTH exome AF: 0.00350

GnomAD4 exome AF: 0.00376 AC: 5490 AN: 1460328 Hom.: 17 Cov.: 32 AF XY: 0.00373 AC XY: 2711 AN XY: 726500

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00349

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00161

Gnomad4 NFE exome AF: 0.00454

Gnomad4 OTH exome AF: 0.00293

GnomAD4 genome AF: 0.00293 AC: 446 AN: 152304 Hom.: 2 Cov.: 32 AF XY: 0.00273 AC XY: 203 AN XY: 74480

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00468

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00441 Hom.: 1

Bravo AF: 0.00315

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000964 AC: 4

ESP6500EA AF: 0.00418 AC: 35

ExAC AF: 0.00314 AC: 380

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00485

EpiControl AF: 0.00510

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2018	This variant is associated with the following publications: (PMID: 18429043, 32707200) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CDH23: BP4, BS2 -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 11, 2013	The Glu960Lys variant in CDH23: 0.4% (35/8368) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs111033458). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 12, 2022	Variant summary: CDH23 c.2878G>A (p.Glu960Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.003 in 245864 control chromosomes, predominantly at a frequency of 0.005 within the Non-Finnish European subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH23 causing Usher Syndrome phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Although reported in the literature, to our knowledge, no penetrant association of c.2878G>A in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories report a majority consensus as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

CDH23-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 04, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Usher syndrome type 1D Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Usher syndrome type 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 15, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0068	T;T;T;.;T;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.090
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.68	T;T;T;T;T;T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.010	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	.;.;N;.;.;.
PrimateAI	Benign	0.38	T
REVEL	Benign	0.091
Sift4G	Benign	0.60	T;T;.;T;T;.
Polyphen		0.0040	.;.;B;.;.;.
Vest4		0.43
MVP		0.72
ClinPred		0.014	T
GERP RS		4.6
Varity_R		0.066
gMVP		0.39

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: rs111033458; hg19: chr10-73464812; COSMIC: COSV54934710;