16-3015379-G-T

Variant names:

• chr16-3015379-G-T
• NM_021195.5:c.643C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021195.5(CLDN6):​c.643C>A​(p.Pro215Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000073 in 1,370,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: CLDN6 NM_021195.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.87

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13502637).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN6	NM_021195.5	c.643C>A	p.Pro215Thr	missense_variant	Exon 2 of 2	ENST00000328796.5	NP_067018.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN6	ENST00000328796.5	c.643C>A	p.Pro215Thr	missense_variant	Exon 2 of 2	1	NM_021195.5	ENSP00000328674.4
CLDN6	ENST00000396925.1	c.643C>A	p.Pro215Thr	missense_variant	Exon 3 of 3	5		ENSP00000380131.1
CLDN6	ENST00000572154.1	c.94-198C>A		intron_variant	Intron 2 of 2	3		ENSP00000458783.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.30e-7 AC: 1 AN: 1370672 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 672570

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.34e-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

Sep 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.643C>A (p.P215T) alteration is located in exon 2 (coding exon 1) of the CLDN6 gene. This alteration results from a C to A substitution at nucleotide position 643, causing the proline (P) at amino acid position 215 to be replaced by a threonine (T). 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	Benign	0.10
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Benign	0.61
DEOGEN2	Benign	0.069	T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.069
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.68	.;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.68	N;N
REVEL	Benign	0.26
Sift	Benign	0.20	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.010	B;B
Vest4		0.079
MutPred		0.16		Gain of phosphorylation at P215 (P = 0.0537);Gain of phosphorylation at P215 (P = 0.0537);
MVP		0.71
MPC		0.56
ClinPred		0.21	T
GERP RS		4.8
Varity_R		0.12
gMVP		0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-3065380;