16-3015390-G-T

Variant names:

• chr16-3015390-G-T
• rs200821404
• NM_021195.5:c.632C>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.632C>A​(p.Pro211His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,372,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P211L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: CLDN6 NM_021195.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.653
• 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=0.12414992).

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.632C>A	p.Pro211His	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.632C>A	p.Pro211His	missense	Exon 2 of 2	ENSP00000328674.4	P56747
	CLDN6	ENST00000396925.1	TSL:5	c.632C>A	p.Pro211His	missense	Exon 3 of 3	ENSP00000380131.1	P56747
	CLDN6	ENST00000939715.1		c.632C>A	p.Pro211His	missense	Exon 2 of 2	ENSP00000609774.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1372534 Hom.: 0 Cov.: 30 AF XY: 0.00000148 AC XY: 1 AN XY: 673784

African (AFR) AF: 0.0000330 AC: 1 AN: 30348

American (AMR) AF: 0.00 AC: 0 AN: 29656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39052

South Asian (SAS) AF: 0.00 AC: 0 AN: 70990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5324

European-Non Finnish (NFE) AF: 9.34e-7 AC: 1 AN: 1071022

Other (OTH) AF: 0.00 AC: 0 AN: 56444

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.055
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.65
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.24
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.010	D
Polyphen		0.0010	B
Vest4		0.11
MutPred		0.24		Loss of glycosylation at P211 (P = 0.0309)
MVP		0.71
MPC		0.19
ClinPred		0.16	T
GERP RS		4.8
Varity_R		0.14
gMVP		0.65
Mutation Taster		=94/6	polymorphism

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

dbSNP: rs200821404; hg19: chr16-3065391;