chr16-3015559-C-T

Variant names:

• chr16-3015559-C-T
• NM_021195.5:c.463G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021195.5(CLDN6):​c.463G>A​(p.Ala155Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CLDN6 NM_021195.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0400
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21466696).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021195.5. 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
	CLDN6	NM_021195.5	MANE Select	c.463G>A	p.Ala155Thr	missense	Exon 2 of 2	NP_067018.2	P56747

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN6	ENST00000328796.5	TSL:1 MANE Select	c.463G>A	p.Ala155Thr	missense	Exon 2 of 2	ENSP00000328674.4	P56747
	CLDN6	ENST00000396925.1	TSL:5	c.463G>A	p.Ala155Thr	missense	Exon 3 of 3	ENSP00000380131.1	P56747
	CLDN6	ENST00000939715.1		c.463G>A	p.Ala155Thr	missense	Exon 2 of 2	ENSP00000609774.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460736 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726652

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111948

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.040
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.29
Sift	Benign	0.077	T
Sift4G	Benign	0.19	T
Polyphen		0.0050	B
Vest4		0.33
MutPred		0.32		Loss of ubiquitination at K157 (P = 0.0877)
MVP		0.42
MPC		0.42
ClinPred		0.75	D
GERP RS		-0.10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.43

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

Other links and lift over

hg19: chr16-3065560;