Genetic Variant CLDN9:p.Pro74Pro (chr16-3013584-G-A) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_020982.4(CLDN9):c.222G>A(p.Pro74Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00623 in 1,613,932 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0057 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0063 ( 60 hom. )

Consequence

CLDN9
NM_020982.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.369

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 16-3013584-G-A is Benign according to our data. Variant chr16-3013584-G-A is described in ClinVar as [Benign]. Clinvar id is 2498646.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.369 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00629 (9194/1461622) while in subpopulation MID AF= 0.0222 (127/5722). AF 95% confidence interval is 0.0191. There are 60 homozygotes in gnomad4_exome. There are 4757 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN9	NM_020982.4 link	c.222G>A	p.Pro74Pro	synonymous_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.222G>A	p.Pro74Pro	synonymous_variant	Exon 1 of 1	6	NM_020982.4	ENSP00000398017.2		O95484

Frequencies

GnomAD3 genomes

AF:

0.00569

AC:

866

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000892

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.00550

Gnomad ASJ

AF:

0.00865

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00869

Gnomad FIN

AF:

0.0247

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00513

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00707

AC:

1772

AN:

250802

Hom.:

AF XY:

0.00761

AC XY:

1033

AN XY:

135734

show subpopulations

Gnomad AFR exome

AF:

0.000924

Gnomad AMR exome

AF:

0.00605

Gnomad ASJ exome

AF:

0.00906

Gnomad EAS exome

AF:

0.00169

Gnomad SAS exome

AF:

0.0106

Gnomad FIN exome

AF:

0.0201

Gnomad NFE exome

AF:

0.00536

Gnomad OTH exome

AF:

0.00983

GnomAD4 exome

AF:

0.00629

AC:

9194

AN:

1461622

Hom.:

Cov.:

AF XY:

0.00654

AC XY:

4757

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.000956

Gnomad4 AMR exome

AF:

0.00642

Gnomad4 ASJ exome

AF:

0.00842

Gnomad4 EAS exome

AF:

0.00254

Gnomad4 SAS exome

AF:

0.0121

Gnomad4 FIN exome

AF:

0.0175

Gnomad4 NFE exome

AF:

0.00541

Gnomad4 OTH exome

AF:

0.00727

GnomAD4 genome

AF:

0.00569

AC:

867

AN:

152310

Hom.:

Cov.:

AF XY:

0.00683

AC XY:

509

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000890

Gnomad4 AMR

AF:

0.00549

Gnomad4 ASJ

AF:

0.00865

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.00890

Gnomad4 FIN

AF:

0.0247

Gnomad4 NFE

AF:

0.00513

Gnomad4 OTH

AF:

0.00614

Alfa

AF:

0.00436

Hom.:

Bravo

AF:

0.00461

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00556

EpiControl

AF:

0.00575

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CLDN9: BP4, BP7, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

7.8

DANN

Benign

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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