7-101234407-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_014343.3(CLDN15):​c.253G>A​(p.Ala85Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,612,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CLDN15
NM_014343.3 missense

Scores

5
13
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.67
Variant links:
Genes affected
CLDN15 (HGNC:2036): (claudin 15) This gene encodes a member of the claudin family. Claudins are integral membrane proteins and components of tight junction strands. Tight junction strands serve as a physical barrier to prevent solutes and water from passing freely through the paracellular space between epithelial or endothelial cell sheets, and also play critical roles in maintaining cell polarity and signal transductions. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jun 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CLDN15NM_014343.3 linkc.253G>A p.Ala85Thr missense_variant Exon 2 of 5 ENST00000308344.10 NP_055158.1 P56746
CLDN15NM_001185080.2 linkc.253G>A p.Ala85Thr missense_variant Exon 3 of 6 NP_001172009.1 P56746

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CLDN15ENST00000308344.10 linkc.253G>A p.Ala85Thr missense_variant Exon 2 of 5 1 NM_014343.3 ENSP00000308870.5 P56746

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152044
Hom.:
0
Cov.:
32
show subpopulations
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
251026
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135696
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000110
AC:
16
AN:
1460826
Hom.:
0
Cov.:
30
AF XY:
0.0000165
AC XY:
12
AN XY:
726752
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:
0.0000135
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152044
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74258
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000519
AC:
2
ExAC
AF:
0.0000165
AC:
2

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Oct 13, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.253G>A (p.A85T) alteration is located in exon 3 (coding exon 2) of the CLDN15 gene. This alteration results from a G to A substitution at nucleotide position 253, causing the alanine (A) at amino acid position 85 to be replaced by a threonine (T). 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
0.36
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.020
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.91
D;D
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Uncertain
0.95
.;D
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.93
D;D
MetaSVM
Pathogenic
0.92
D
MutationAssessor
Pathogenic
3.0
M;M
PrimateAI
Uncertain
0.49
T
PROVEAN
Uncertain
-2.4
N;N
REVEL
Uncertain
0.63
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.0050
D;D
Polyphen
0.96
D;D
Vest4
0.73
MutPred
0.77
Gain of catalytic residue at T84 (P = 0.3157);Gain of catalytic residue at T84 (P = 0.3157);
MVP
0.83
MPC
0.93
ClinPred
0.94
D
GERP RS
5.1
Varity_R
0.36
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
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: rs765578247; hg19: chr7-100877688; API