rs143282422

Positions:

• chr10-71617355-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_022124.6(CDH23):​c.1096G>A​(p.Ala366Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00923 in 1,613,862 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A366A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0065 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (128 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:14
• Conservation: PhyloP100: 9.24

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008493274).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00653 (994/152264) while in subpopulation NFE AF= 0.00912 (620/68016). AF 95% confidence interval is 0.00852. There are 7 homozygotes in gnomad4. There are 434 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.1096G>A	p.Ala366Thr	missense_variant	11/70	ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.1096G>A	p.Ala366Thr	missense_variant	11/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.00653 AC: 994 AN: 152146 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00911

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00732 AC: 1825 AN: 249204 Hom.: 22 AF XY: 0.00726 AC XY: 981 AN XY: 135174

Gnomad AFR exome AF: 0.00187

Gnomad AMR exome AF: 0.00452

Gnomad ASJ exome AF: 0.0487

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00167

Gnomad FIN exome AF: 0.000979

Gnomad NFE exome AF: 0.00898

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.00952 AC: 13910 AN: 1461598 Hom.: 128 Cov.: 31 AF XY: 0.00943 AC XY: 6857 AN XY: 727090

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.00517

Gnomad4 ASJ exome AF: 0.0535

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00210

Gnomad4 FIN exome AF: 0.00128

Gnomad4 NFE exome AF: 0.0102

Gnomad4 OTH exome AF: 0.0104

GnomAD4 genome AF: 0.00653 AC: 994 AN: 152264 Hom.: 7 Cov.: 32 AF XY: 0.00583 AC XY: 434 AN XY: 74450

Gnomad4 AFR AF: 0.00202

Gnomad4 AMR AF: 0.00542

Gnomad4 ASJ AF: 0.0452

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00912

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.0109 Hom.: 30

Bravo AF: 0.00730

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00389 AC: 17

ESP6500EA AF: 0.0103 AC: 88

ExAC AF: 0.00696 AC: 844

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00965

EpiControl AF: 0.0107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 30, 2013	Ala366Thr in Exon 11A of CDH23: This variant is not expected to have clinical si gnificance because it has been identified in 1.0% (88/8560) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs143282422). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 24, 2020	- -
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	GeneDx	Jan 16, 2018	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	Eurofins Ntd Llc (ga)	Jan 13, 2015	- -

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 07, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CDH23: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Usher syndrome type 1D 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

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. -

Nonsyndromic genetic hearing loss Benign:1

Benign, criteria provided, single submitter

clinical testing

INGEBI, INGEBI / CONICET

Jul 15, 2021

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria:The filter allele frequency of c.1096 G>A (A366T) in CDH23 gene is 500/10356 (4,5% with 95% CI) in Ashkenazi Jewish ethnic group in gnomad population database, witch meets the criteria for BA1. Computational evidence is not suffcient to apply to PP3 either BP4 (REVEL:0.198). This variant has been identifiec with c.3293A>G in CDH23 gene in an Usher type 1D patient with unkown phase (PMID:18429043 ). Since c.3293A>G is classified as VUS, PM3 is not applied. Also, A366T was detected in hetercygous state in three usher patients without other variants (PMID: 15660226). Considering BA1, the variant is classified as Benign. -

Usher syndrome type 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 15, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.0025	T;T;T;.;.;.;T;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0085	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.98	N;.;N;.;N;.;.;.;.
REVEL	Benign	0.20
Sift	Benign	0.14	T;.;T;.;T;.;.;.;.
Sift4G	Uncertain	0.012	D;D;.;T;D;T;D;.;.
Polyphen		1.0, 1.0	.;.;D;D;.;.;.;.;.
Vest4		0.79
MVP		0.76
ClinPred		0.032	T
GERP RS		5.2
Varity_R		0.30
gMVP		0.40

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: rs143282422; hg19: chr10-73377112;