Genetic Variant CLDN5:p.Val41Met (chr22-19524135-C-T) – ACMG Classification: Pathogenic (15 pts)

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong

The NM_001363066.2(CLDN5):c.121G>A(p.Val41Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

CLDN5
NM_001363066.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.76

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: G2P

CLDN5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PM1

In a topological_domain Extracellular (size 52) in uniprot entity CLD5_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001363066.2

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.4376 (below the threshold of 3.09). Trascript score misZ: 1.274 (below the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.904

PP5

Variant 22-19524135-C-T is Pathogenic according to our data. Variant chr22-19524135-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3340659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363066.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLDN5	NM_001363066.2	MANE Select	c.121G>A	p.Val41Met	missense	Exon 1 of 1	NP_001349995.1	O00501
CLDN5	NM_001130861.1		c.376G>A	p.Val126Met	missense	Exon 1 of 1	NP_001124333.1	O00501
CLDN5	NM_001363067.2		c.376G>A	p.Val126Met	missense	Exon 2 of 2	NP_001349996.1	D3DX19

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLDN5	ENST00000618236.2	TSL:6 MANE Select	c.121G>A	p.Val41Met	missense	Exon 1 of 1	ENSP00000480623.1	O00501
CLDN5	ENST00000403084.1	TSL:6	c.376G>A	p.Val126Met	missense	Exon 1 of 1	ENSP00000384554.1	D3DX19
CLDN5	ENST00000406028.1	TSL:2	c.376G>A	p.Val126Met	missense	Exon 2 of 2	ENSP00000385477.1	D3DX19

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurodevelopmental disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.90

MetaSVM

Pathogenic

0.86

MutationAssessor

Pathogenic

2.9

PhyloP100

7.8

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-2.7

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0030

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.74

MutPred

0.76

Loss of catalytic residue at V126 (P = 0.0152)

MVP

0.85

MPC

2.2

ClinPred

0.99

GERP RS

5.2

PromoterAI

0.0031

Neutral

(source)

Varity_R

0.35

gMVP

0.75

Mutation Taster

=50/50

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over