rs200786014

Positions:

chr10-71784893-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_022124.6(CDH23):c.5505G>A(p.Met1835Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000744 in 1,613,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.27

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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01736474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6 linkuse as main transcript	c.5505G>A	p.Met1835Ile	missense_variant, splice_region_variant	43/70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.5505G>A	p.Met1835Ile	missense_variant, splice_region_variant	43/70	5	NM_022124.6	ENSP00000224721	P1	Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.000467

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000120

AC:

AN:

249294

Hom.:

AF XY:

0.0000887

AC XY:

AN XY:

135242

show subpopulations

Gnomad AFR exome

AF:

0.00161

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1461100

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

726888

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.000466

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00161

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000633

Hom.:

Bravo

AF:

0.000536

ESP6500AA

AF:

0.00117

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000149

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 08, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 06, 2022	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1835 of the CDH23 protein (p.Met1835Ile). This variant is present in population databases (rs200786014, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 45983). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Childhood onset hearing loss

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

National Institute on Deafness and Communication Disorders, National Institutes of Health

Jul 08, 2021

BP4 / Modifications from PMID: 30311386 for classification: The genetic causes of hearing loss have not yet been well characterized in the Yoruba population, and the information regarding variant MAF in this population is still limited, so we did not exclude any variant based on their "high" MAF. PP3 criteria was applied even if the REVEL score was below 0.7, if at least two of the pathogenicity prediction algorithms used predicted that the variant was damaging or likely damaging. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 10, 2014

p.Met1835Ile in exon 43 of CDH23: This variant is not expected to have clinical significance due to a lack of conservation across species. Of note, the platypus and seven bird species have an isoleucine (Ile) at this position despite high n earby amino acid conservation. It has been identified in 0.1% (5/4282) of Africa n American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.wash ington.edu/EVS/; dbSNP rs200786014). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0059

T;T

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.017

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.57

.;N

MutationTaster

Benign

0.83

PrimateAI

Uncertain

0.49

REVEL

Benign

0.10

Sift4G

Benign

0.20

T;.

Polyphen

0.0090

.;B

Vest4

0.29

MutPred

0.42

Loss of disorder (P = 0.084);Loss of disorder (P = 0.084);

MVP

0.56

ClinPred

0.014

GERP RS

3.4

Varity_R

0.38

gMVP

0.33

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