rs144688588

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP6

The NM_022124.6(CDH23):c.9629T>C(p.Ile3210Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000505 in 1,613,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I3210V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00053 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:5

Conservation

PhyloP100: 7.96

Variant links:

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]

CDH23 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2721909).

BP6

Variant 10-71812886-T-C is Benign according to our data. Variant chr10-71812886-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178315.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6 linkuse as main transcript	c.9629T>C	p.Ile3210Thr	missense_variant	68/70	ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.9629T>C	p.Ile3210Thr	missense_variant	68/70	5	NM_022124.6	P1	Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000331

AC:

AN:

247764

Hom.:

AF XY:

0.000364

AC XY:

AN XY:

134478

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.000175

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000372

Gnomad NFE exome

AF:

0.000543

Gnomad OTH exome

AF:

0.000829

GnomAD4 exome

AF:

0.000531

AC:

776

AN:

1461140

Hom.:

Cov.:

AF XY:

0.000535

AC XY:

389

AN XY:

726808

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000338

Gnomad4 NFE exome

AF:

0.000646

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000256

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000471

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000525

Hom.:

Bravo

AF:

0.000261

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000357

AC:

ExAC

AF:

0.000388

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000535

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2022	Identified with a second CDH23 variant, phase unknown, in an individual with Usher syndrome (Selcen et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23794683) -
Uncertain significance, 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	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 09, 2023	PM2_supporting -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 01, 2020

The p.Ile3210Thr variant in CDH23 has been previously identified by our laboratory in 2 probands with hearing loss; however, a variant affecting the remaining copy of CDH23 was not identified in either proband, and an alternate explanation of the hearing loss was identified in one proband. This variant has been reported in ClinVar (Variation ID 178315), and has been identified in 0.05% (67/127654) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Ile3210Thr variant may impact the protein, though this information is not predictive e nough to determine pathogenicity. In summary, the clinical significance of the p .Ile3210Thr variant is uncertain. ACMG/AMP criteria applied: PM2_Supporting, BP4. -

Nonsyndromic Hearing Loss, Recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Usher syndrome type 1D

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Usher syndrome type 1

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Retinitis pigmentosa-deafness syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Atypical Gaucher Disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Combined PSAP deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Galactosylceramide beta-galactosidase deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Metachromatic leukodystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Pathogenic

0.25

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.012

T;T;.;.

Eigen

Uncertain

0.62

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.27

T;T;T;T

MetaSVM

Uncertain

0.31

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.84

Sift4G

Pathogenic

0.0

D;.;D;D

Polyphen

0.96

.;D;.;.

Vest4

0.91

MVP

0.92

MPC

0.22

ClinPred

0.068

GERP RS

6.1

Varity_R

0.29

gMVP

0.65

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over