16-3015390-G-C

Variant names:

• chr16-3015390-G-C
• rs200821404
• NM_021195.5:c.632C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_021195.5(CLDN6):​c.632C>G​(p.Pro211Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000275 in 1,524,584 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: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039408296).

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>G	p.Pro211Arg	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>G	p.Pro211Arg	missense	Exon 2 of 2	ENSP00000328674.4	P56747
	CLDN6	ENST00000396925.1	TSL:5	c.632C>G	p.Pro211Arg	missense	Exon 3 of 3	ENSP00000380131.1	P56747
	CLDN6	ENST00000939715.1		c.632C>G	p.Pro211Arg	missense	Exon 2 of 2	ENSP00000609774.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152050 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000723 AC: 13 AN: 179748 AF XY: 0.0000528

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000733

GnomAD4 exome AF: 0.0000270 AC: 37 AN: 1372534 Hom.: 0 Cov.: 30 AF XY: 0.0000327 AC XY: 22 AN XY: 673784

African (AFR) AF: 0.00 AC: 0 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: 0.000423 AC: 30 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: 0.00000280 AC: 3 AN: 1071022

Other (OTH) AF: 0.0000709 AC: 4 AN: 56444

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152050 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74266

African (AFR) AF: 0.00 AC: 0 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000668 AC: 8

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Benign	0.76
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.097
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.65
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.22
Sift	Benign	0.27	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.22
MutPred		0.31		Gain of MoRF binding (P = 0.0044)
MVP		0.69
MPC		0.38
ClinPred		0.039	T
GERP RS		4.8
Varity_R		0.12
gMVP		0.73
Mutation Taster		=97/3	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;