Genetic Variant CLDN9:p.Arg116Cys (chr16-3013708-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP5_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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R116H) has been classified as Uncertain significance.

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

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

hearing loss, autosomal recessive 116
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

CLDN9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020982.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN9	NM_020982.4	MANE Select	c.346C>T	p.Arg116Cys	missense	Exon 1 of 1	NP_066192.1	O95484

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN9	ENST00000445369.3	TSL:6 MANE Select	c.346C>T	p.Arg116Cys	missense	Exon 1 of 1	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

GnomAD2 exomes

AF:

0.000439

AC:

110

AN:

250798

AF XY:

0.000457

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 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

African (AFR)

AF:

0.000388

AC:

AN:

33480

American (AMR)

AF:

0.000112

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00777

AC:

203

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000566

AC:

AN:

53020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000791

AC:

AN:

1111978

Other (OTH)

AF:

0.000480

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

100

125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000394

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.000603

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00721

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68016

Other (OTH)

AF:

0.000958

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000540

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

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hearing loss, autosomal recessive 116 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

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

PhyloP100

2.1

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

Mutation Taster

=66/34

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over