chr7-73769403-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001306.4(CLDN3):​c.647G>T​(p.Arg216Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000622 in 1,446,178 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: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

CLDN3
NM_001306.4 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.18
Variant links:
Genes affected
CLDN3 (HGNC:2045): (claudin 3) 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. The protein encoded by this intronless gene, a member of the claudin family, is an integral membrane protein and a component of tight junction strands. It is also a low-affinity receptor for Clostridium perfringens enterotoxin, and shares aa sequence similarity with a putative apoptosis-related protein found in rat. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.15099543).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CLDN3NM_001306.4 linkc.647G>T p.Arg216Leu missense_variant Exon 1 of 1 ENST00000395145.3 NP_001297.1 O15551Q75L79

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CLDN3ENST00000395145.3 linkc.647G>T p.Arg216Leu missense_variant Exon 1 of 1 6 NM_001306.4 ENSP00000378577.2 O15551

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000622
AC:
9
AN:
1446178
Hom.:
0
Cov.:
31
AF XY:
0.00000695
AC XY:
5
AN XY:
719840
show subpopulations
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:
0.00000720
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 25, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.647G>T (p.R216L) alteration is located in exon 1 (coding exon 1) of the CLDN3 gene. This alteration results from a G to T substitution at nucleotide position 647, causing the arginine (R) at amino acid position 216 to be replaced by a leucine (L). 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
Uncertain
0.51
BayesDel_addAF
Uncertain
0.089
D
BayesDel_noAF
Benign
-0.11
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.061
T
Eigen
Benign
-0.15
Eigen_PC
Benign
-0.015
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.67
T
M_CAP
Benign
0.064
D
MetaRNN
Benign
0.15
T
MetaSVM
Benign
-0.38
T
MutationAssessor
Benign
1.3
L
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-2.2
N
REVEL
Uncertain
0.50
Sift
Benign
0.038
D
Sift4G
Benign
0.37
T
Polyphen
0.29
B
Vest4
0.26
MutPred
0.30
Loss of disorder (P = 0.0497);
MVP
0.61
MPC
0.79
ClinPred
0.83
D
GERP RS
4.6
Varity_R
0.28
gMVP
0.42

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs868906959; hg19: chr7-73183733; API