16-3015618-G-C

Position:

• chr16-3015618-G-C

Variant summary

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

The NM_021195.5(CLDN6):​c.404C>G​(p.Pro135Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLDN6 NM_021195.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

CLDN6 (HGNC:2048): (claudin 6) Tight junctions represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. These junctions are comprised of sets of continuous networking strands in the outwardly facing cytoplasmic leaflet, with complementary grooves in the inwardly facing extracytoplasmic leaflet. This gene encodes a component of tight junction strands, which is a member of the claudin family. The protein is an integral membrane protein and is one of the entry cofactors for hepatitis C virus. The gene methylation may be involved in esophageal tumorigenesis. This gene is adjacent to another family member CLDN9 on chromosome 16.[provided by RefSeq, Aug 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, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLDN6	NM_021195.5	c.404C>G	p.Pro135Arg	missense_variant	2/2	ENST00000328796.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLDN6	ENST00000328796.5	c.404C>G	p.Pro135Arg	missense_variant	2/2	1	NM_021195.5	P1
CLDN6	ENST00000396925.1	c.404C>G	p.Pro135Arg	missense_variant	3/3	5		P1
CLDN6	ENST00000572154.1	c.93+311C>G		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2021

The c.404C>G (p.P135R) alteration is located in exon 2 (coding exon 1) of the CLDN6 gene. This alteration results from a C to G substitution at nucleotide position 404, causing the proline (P) at amino acid position 135 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	0.98
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-8.7	D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.82
MutPred		0.85		Gain of MoRF binding (P = 0.0314);Gain of MoRF binding (P = 0.0314);
MVP		0.96
MPC		0.69
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-3065619;