NM_021195.5:c.295C>T

Variant summary

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

The NM_021195.5(CLDN6):​c.295C>T​(p.Leu99Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. L99V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CLDN6
NM_021195.5 missense

Scores

4
15

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.269
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]

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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=0.1492649).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CLDN6NM_021195.5 linkc.295C>T p.Leu99Phe missense_variant Exon 2 of 2 ENST00000328796.5 NP_067018.2 P56747

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CLDN6ENST00000328796.5 linkc.295C>T p.Leu99Phe missense_variant Exon 2 of 2 1 NM_021195.5 ENSP00000328674.4 P56747
CLDN6ENST00000396925.1 linkc.295C>T p.Leu99Phe missense_variant Exon 3 of 3 5 ENSP00000380131.1 P56747
CLDN6ENST00000572154.1 linkc.93+202C>T intron_variant Intron 2 of 2 3 ENSP00000458783.1 I3L1E7

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461566
Hom.:
0
Cov.:
35
AF XY:
0.00000275
AC XY:
2
AN XY:
727066
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.039
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.57
D;D
Eigen
Benign
-0.51
Eigen_PC
Benign
-0.44
FATHMM_MKL
Benign
0.18
N
LIST_S2
Uncertain
0.90
.;D
M_CAP
Benign
0.056
D
MetaRNN
Benign
0.15
T;T
MetaSVM
Benign
-0.39
T
MutationAssessor
Benign
1.2
L;L
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-2.3
N;N
REVEL
Benign
0.20
Sift
Benign
0.24
T;T
Sift4G
Benign
0.38
T;T
Polyphen
0.026
B;B
Vest4
0.15
MutPred
0.46
Gain of catalytic residue at L99 (P = 0.0374);Gain of catalytic residue at L99 (P = 0.0374);
MVP
0.53
MPC
0.48
ClinPred
0.75
D
GERP RS
2.6
Varity_R
0.11
gMVP
0.32

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-3065728; COSMIC: COSV58509545; COSMIC: COSV58509545; API