16-3013681-T-C

Variant names:

• chr16-3013681-T-C
• rs199692917
• NM_020982.4:c.319T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_020982.4(CLDN9):​c.319T>C​(p.Cys107Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CLDN9 NM_020982.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.01

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN9	NM_020982.4	c.319T>C	p.Cys107Arg	missense_variant	Exon 1 of 1	ENST00000445369.3	NP_066192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN9	ENST00000445369.3	c.319T>C	p.Cys107Arg	missense_variant	Exon 1 of 1	6	NM_020982.4	ENSP00000398017.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250904 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461594 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.319T>C (p.C107R) alteration is located in exon 1 (coding exon 1) of the CLDN9 gene. This alteration results from a T to C substitution at nucleotide position 319, causing the cysteine (C) at amino acid position 107 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.8	H
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.78		Gain of disorder (P = 0.0051);
MVP		0.84
MPC		0.20
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.97
gMVP		0.56

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

Other links and lift over

dbSNP: rs199692917; hg19: chr16-3063682;