Genetic Variant CLDN9:p.Arg116Cys (chr16-3013708-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4

The NM_020982.4(CLDN9):c.346C>T(p.Arg116Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000249 in 1,613,608 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

CLDN9
NM_020982.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.13

Variant links:

Genes affected

CLDN9 (HGNC:2051): (claudin 9) This gene encodes a member of the claudin family. Claudins are integral membrane proteins and components of tight junction strands. Tight junction strands serve as a physical barrier to prevent solutes and water from passing freely through the paracellular space between epithelial or endothelial cell sheets, and also play critical roles in maintaining cell polarity and signal transductions. This protein is one of the entry cofactors for hepatitis C virus. Mouse studies revealed that this gene is required for the preservation of sensory cells in the hearing organ and the gene deficiency is associated with deafness. [provided by RefSeq, Jun 2010]

CLDN9 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-3013708-C-T is Pathogenic according to our data. Variant chr16-3013708-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3250379.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.040551573). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN9	NM_020982.4 link	c.346C>T	p.Arg116Cys	missense_variant	Exon 1 of 1	ENST00000445369.3	NP_066192.1	O95484

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN9	ENST00000445369.3 link	c.346C>T	p.Arg116Cys	missense_variant	Exon 1 of 1	6	NM_020982.4	ENSP00000398017.2		O95484

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00721

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000439

AC:

110

AN:

250798

Hom.:

AF XY:

0.000457

AC XY:

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00777

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000234

AC:

342

AN:

1461426

Hom.:

Cov.:

AF XY:

0.000237

AC XY:

172

AN XY:

727024

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00777

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000566

Gnomad4 NFE exome

AF:

0.0000791

Gnomad4 OTH exome

AF:

0.000480

GnomAD4 genome

AF:

0.000394

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.000603

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00721

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000958

Alfa

AF:

0.000495

Hom.:

Bravo

AF:

0.000468

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000313

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hearing loss, autosomal recessive 116

Pathogenic:1

May 01, 2024

Laboratory of Prof. Karen Avraham, Tel Aviv University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Homozygosity of a variant predicted deleterious by all prediction programs. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.26

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.041

MetaSVM

Uncertain

0.66

MutationAssessor

Pathogenic

3.0

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-5.9

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.54

MVP

0.82

MPC

0.029

ClinPred

0.13

GERP RS

2.6

Varity_R

0.64

gMVP

0.71

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