dbSNP rs397517365: CDH23:p.Gln3029Pro (chr10-71811323-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022124.6(CDH23):c.9086A>C(p.Gln3029Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q3029Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.09

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 12
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Usher syndrome type 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 1D
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CDH23 links:

LOC124902446 (HGNC:):

LOC124902446 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CDH23	NM_022124.6 link	c.9086A>C	p.Gln3029Pro	missense_variant	Exon 63 of 70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171933.1 link	c.2366A>C	p.Gln789Pro	missense_variant	Exon 16 of 23		NP_001165404.1
CDH23	NM_001171934.1 link	c.2366A>C	p.Gln789Pro	missense_variant	Exon 16 of 22		NP_001165405.1
LOC124902446	XR_007062185.1 link	n.1267+169T>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.9086A>C	p.Gln3029Pro	missense_variant	Exon 63 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 07, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Gln3029Pro vari ant in CDH23 has not been reported in the literature nor previously identified b y our laboratory. Computational analyses (biochemical amino acid properties, hom ology, PolyPhen2, SIFT, AlignGVGD) do not provide strong support for or against pathogenicity. In the absence of additional information, such as identification of a second CDH23 variant in this individual, control data, segregation studies or functional analysis, the clinical significance of this variant cannot be dete rmined at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.025

T;T;.;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.92

D;D;D;D

M_CAP

Benign

0.029

MetaRNN

Uncertain

0.74

D;D;D;D

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.8

.;L;.;.

PhyloP100

6.1

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.3

.;.;.;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.0070

.;.;.;D

Sift4G

Pathogenic

0.0

D;.;D;D

Polyphen

0.83

.;P;.;.

Vest4

0.92

MutPred

0.56

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;.;

MVP

0.78

MPC

0.42

ClinPred

0.98

GERP RS

4.5

Varity_R

0.49

gMVP

0.87

Mutation Taster

=39/61

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over