22-19524420-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The NM_003277.4(CLDN5):​c.91G>A​(p.Gly31Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000038 in 1,446,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

CLDN5
NM_003277.4 missense

Scores

1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.187
Variant links:
Genes affected
CLDN5 (HGNC:2047): (claudin 5) 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. Mutations in this gene have been found in patients with velocardiofacial syndrome. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2018]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1
In a chain Claudin-5 (size 217) in uniprot entity CLD5_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_003277.4
BP4
Computational evidence support a benign effect (MetaRNN=0.048207164).
BS2
High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CLDN5NM_001130861.1 linkc.91G>A p.Gly31Ser missense_variant Exon 1 of 1 NP_001124333.1 O00501D3DX19
CLDN5NM_001363067.2 linkc.91G>A p.Gly31Ser missense_variant Exon 2 of 2 NP_001349996.1
CLDN5NM_003277.4 linkc.91G>A p.Gly31Ser missense_variant Exon 2 of 2 NP_003268.2 O00501D3DX19
CLDN5NM_001363066.2 linkc.-165G>A upstream_gene_variant ENST00000618236.2 NP_001349995.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CLDN5ENST00000403084.1 linkc.91G>A p.Gly31Ser missense_variant Exon 1 of 1 6 ENSP00000384554.1 D3DX19
CLDN5ENST00000406028.1 linkc.91G>A p.Gly31Ser missense_variant Exon 2 of 2 2 ENSP00000385477.1 D3DX19
CLDN5ENST00000413119.2 linkc.91G>A p.Gly31Ser missense_variant Exon 2 of 2 2 ENSP00000400612.2 D3DX19
CLDN5ENST00000618236.2 linkc.-165G>A upstream_gene_variant 6 NM_001363066.2 ENSP00000480623.1 O00501

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152216
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000735
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000646
AC:
4
AN:
61892
Hom.:
0
AF XY:
0.0000960
AC XY:
3
AN XY:
31248
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:
0.000172
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000371
AC:
48
AN:
1294334
Hom.:
0
Cov.:
34
AF XY:
0.0000446
AC XY:
28
AN XY:
628172
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:
0.0000160
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000271
Gnomad4 OTH exome
AF:
0.0000375
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152216
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.000478
Bravo
AF:
0.0000642
ExAC
AF:
0.0000453
AC:
1

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Dec 21, 2022
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
2.6
DANN
Benign
0.84
DEOGEN2
Benign
0.0053
T;T;T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.028
N
LIST_S2
Benign
0.29
.;.;T
M_CAP
Benign
0.037
D
MetaRNN
Benign
0.048
T;T;T
MetaSVM
Benign
-0.72
T
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-0.21
N;N;N
REVEL
Benign
0.21
Sift
Benign
0.33
T;T;T
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
0.17
B;B;B
Vest4
0.14
MutPred
0.096
Gain of phosphorylation at G31 (P = 0.0215);Gain of phosphorylation at G31 (P = 0.0215);Gain of phosphorylation at G31 (P = 0.0215);
MVP
0.39
MPC
1.0
ClinPred
0.052
T
GERP RS
-10
gMVP
0.069

Splicing

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: rs765505732; hg19: chr22-19511943; COSMIC: COSV54244001; COSMIC: COSV54244001; API