Genetic Variant NM_021195.5:c.643C>A (chr16-3015379-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_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. 15/22 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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.87

Publications

0 publications found

Variant links:

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]

CLDN6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.13502637).

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.643C>A	p.Pro215Thr	missense	Exon 2 of 2	NP_067018.2	P56747

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLDN6	ENST00000328796.5	TSL:1 MANE Select	c.643C>A	p.Pro215Thr	missense	Exon 2 of 2	ENSP00000328674.4	P56747
CLDN6	ENST00000396925.1	TSL:5	c.643C>A	p.Pro215Thr	missense	Exon 3 of 3	ENSP00000380131.1	P56747
CLDN6	ENST00000939715.1		c.643C>A	p.Pro215Thr	missense	Exon 2 of 2	ENSP00000609774.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.30e-7

AC:

AN:

1370672

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

672570

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30302

American (AMR)

AF:

0.00

AC:

AN:

29288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19984

East Asian (EAS)

AF:

0.00

AC:

AN:

39014

South Asian (SAS)

AF:

0.00

AC:

AN:

70680

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5320

European-Non Finnish (NFE)

AF:

9.34e-7

AC:

AN:

1070176

Other (OTH)

AF:

0.00

AC:

AN:

56376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.069

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.069

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.68

M_CAP

Benign

0.044

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.59

MutationAssessor

Benign

0.0

PhyloP100

1.9

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.68

REVEL

Benign

0.26

Sift

Benign

0.20

Sift4G

Benign

0.44

Polyphen

0.010

Vest4

0.079

MutPred

0.16

Gain of phosphorylation at P215 (P = 0.0537)

MVP

0.71

MPC

0.56

ClinPred

0.21

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over