22-19524420-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP2BP4_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. 15/19 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

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

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: 0.26396 (below the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder.

BP4

Computational evidence support a benign effect (MetaRNN=0.048207164).

BS2

High AC in GnomAd4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003277.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLDN5	NM_001130861.1	c.91G>A	p.Gly31Ser	missense	Exon 1 of 1	NP_001124333.1	O00501
CLDN5	NM_001363067.2	c.91G>A	p.Gly31Ser	missense	Exon 2 of 2	NP_001349996.1	D3DX19
CLDN5	NM_003277.4	c.91G>A	p.Gly31Ser	missense	Exon 2 of 2	NP_003268.2	D3DX19

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLDN5	ENST00000403084.1	TSL:6	c.91G>A	p.Gly31Ser	missense	Exon 1 of 1	ENSP00000384554.1	D3DX19
CLDN5	ENST00000406028.1	TSL:2	c.91G>A	p.Gly31Ser	missense	Exon 2 of 2	ENSP00000385477.1	D3DX19
CLDN5	ENST00000413119.2	TSL:2	c.91G>A	p.Gly31Ser	missense	Exon 2 of 2	ENSP00000400612.2	D3DX19

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

GnomAD2 exomes

AF:

0.0000646

AC:

AN:

61892

AF XY:

0.0000960

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 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

African (AFR)

AF:

0.00

AC:

AN:

26660

American (AMR)

AF:

0.00

AC:

AN:

19468

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18522

East Asian (EAS)

AF:

0.00

AC:

AN:

33076

South Asian (SAS)

AF:

0.0000160

AC:

AN:

62370

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44398

Middle Eastern (MID)

AF:

0.00329

AC:

AN:

5162

European-Non Finnish (NFE)

AF:

0.0000271

AC:

AN:

1031368

Other (OTH)

AF:

0.0000375

AC:

AN:

53310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.0000654

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68038

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000453

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.42

CADD

Benign

2.6

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.0053

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.29

M_CAP

Benign

0.037

MetaRNN

Benign

0.048

MetaSVM

Benign

-0.72

PhyloP100

-0.19

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.21

REVEL

Benign

0.21

Sift

Benign

0.33

Sift4G

Pathogenic

0.0

Polyphen

0.17

Vest4

0.14

MutPred

0.096

Gain of phosphorylation at G31 (P = 0.0215)

MVP

0.39

MPC

1.0

ClinPred

0.052

GERP RS

-10

PromoterAI

-0.078

Neutral

(source)

gMVP

0.069

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over