22-19524420-C-T

Variant names:

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

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]

CLDN5 links:

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
CLDN5	NM_001130861.1 link	c.91G>A	p.Gly31Ser	missense_variant	Exon 1 of 1		NP_001124333.1	O00501D3DX19
CLDN5	NM_001363067.2 link	c.91G>A	p.Gly31Ser	missense_variant	Exon 2 of 2		NP_001349996.1
CLDN5	NM_003277.4 link	c.91G>A	p.Gly31Ser	missense_variant	Exon 2 of 2		NP_003268.2	O00501D3DX19
CLDN5	NM_001363066.2 link	c.-165G>A		upstream_gene_variant		ENST00000618236.2	NP_001349995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLDN5	ENST00000403084.1 link	c.91G>A	p.Gly31Ser	missense_variant	Exon 1 of 1	6		ENSP00000384554.1	D3DX19
CLDN5	ENST00000406028.1 link	c.91G>A	p.Gly31Ser	missense_variant	Exon 2 of 2	2		ENSP00000385477.1	D3DX19
CLDN5	ENST00000413119.2 link	c.91G>A	p.Gly31Ser	missense_variant	Exon 2 of 2	2		ENSP00000400612.2	D3DX19
CLDN5	ENST00000618236.2 link	c.-165G>A		upstream_gene_variant		6	NM_001363066.2	ENSP00000480623.1	O00501

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152216

Hom.:

Cov.:

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:

AN:

61892

Hom.:

AF XY:

0.0000960

AC XY:

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:

AN:

1294334

Hom.:

Cov.:

AF XY:

0.0000446

AC XY:

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:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

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:

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

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

LIST_S2

Benign

0.29

.;.;T

M_CAP

Benign

0.037

MetaRNN

Benign

0.048

T;T;T

MetaSVM

Benign

-0.72

PrimateAI

Benign

0.46

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over