rs139409005

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_022124.6(CDH23):c.6809G>A(p.Arg2270His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000598 in 1,612,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. R2270C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00062 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.591

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02303636).

BP6

Variant 10-71797200-G-A is Benign according to our data. Variant chr10-71797200-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178310.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}. Variant chr10-71797200-G-A is described in Lovd as [Likely_benign]. Variant chr10-71797200-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CDH23	NM_022124.6 linkuse as main transcript	c.6809G>A	p.Arg2270His	missense_variant	49/70	ENST00000224721.12
CDH23	NM_001171933.1 linkuse as main transcript	c.89G>A	p.Arg30His	missense_variant	2/23
CDH23	NM_001171934.1 linkuse as main transcript	c.89G>A	p.Arg30His	missense_variant	2/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.6809G>A	p.Arg2270His	missense_variant	49/70	5	NM_022124.6	P1	Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.000960

GnomAD3 exomes

AF:

0.000384

AC:

AN:

247258

Hom.:

AF XY:

0.000328

AC XY:

AN XY:

134118

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000875

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000112

Gnomad SAS exome

AF:

0.000199

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000473

Gnomad OTH exome

AF:

0.000664

GnomAD4 exome

AF:

0.000623

AC:

910

AN:

1460192

Hom.:

Cov.:

AF XY:

0.000607

AC XY:

441

AN XY:

726284

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00103

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.000163

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000720

Gnomad4 OTH exome

AF:

0.000597

GnomAD4 genome

AF:

0.000355

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000529

Gnomad4 OTH

AF:

0.000950

Alfa

AF:

0.000515

Hom.:

Bravo

AF:

0.000366

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000239

AC:

ExAC

AF:

0.000265

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000655

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2023	Reported in an individual with Usher syndrome in published literature; however no additional information was available (Bonnet et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21569298) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 04, 2014

Arg2270His in Exon 49 of CDH23: This variant has been identified in one individu al with Usher syndrome (Bonnet 2011) but has also been detected in 9.4% (205/217 8) chromosomes from a broad population by the 1000 Genomes Project (http://www.1 000genomes.org; dbSNP rs139409005). The arginine (Arg) residue at position 2270 is not conserved through mammals with chimp, tree shrew, mouse, sheep and white rhinoceros having a threonine (Thr). In summary, based on its high frequency in the general population and the presence of the variant amino acid in multiple m ammals, we expect this variant to have no clinical significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.64

Cadd

Benign

5.8

Dann

Uncertain

0.98

DEOGEN2

Benign

0.024

T;T;.;.

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.68

T;T;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.023

T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.23

Sift4G

Uncertain

0.017

D;.;T;T

Polyphen

0.0040

.;B;.;.

Vest4

0.11

MVP

0.61

MPC

0.18

ClinPred

0.033

GERP RS

-1.7

Varity_R

0.055

gMVP

0.32

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