22-19524386-G-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.125C>A(p.Thr42Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,466,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

CLDN5
NM_003277.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.890

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=0.044855714).

BS2

High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN5	NM_001363066.2 link	c.-131C>A		5_prime_UTR_variant	Exon 1 of 1	ENST00000618236.2	NP_001349995.1
CLDN5	NM_001130861.1 link	c.125C>A	p.Thr42Asn	missense_variant	Exon 1 of 1		NP_001124333.1	O00501D3DX19
CLDN5	NM_001363067.2 link	c.125C>A	p.Thr42Asn	missense_variant	Exon 2 of 2		NP_001349996.1
CLDN5	NM_003277.4 link	c.125C>A	p.Thr42Asn	missense_variant	Exon 2 of 2		NP_003268.2	O00501D3DX19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLDN5	ENST00000618236.2 link	c.-131C>A		5_prime_UTR_variant	Exon 1 of 1	6	NM_001363066.2	ENSP00000480623.1	O00501
CLDN5	ENST00000403084.1 link	c.125C>A	p.Thr42Asn	missense_variant	Exon 1 of 1	6		ENSP00000384554.1	D3DX19
CLDN5	ENST00000406028.1 link	c.125C>A	p.Thr42Asn	missense_variant	Exon 2 of 2	2		ENSP00000385477.1	D3DX19
CLDN5	ENST00000413119.2 link	c.125C>A	p.Thr42Asn	missense_variant	Exon 2 of 2	2		ENSP00000400612.2	D3DX19

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000220

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000524

AC:

AN:

76308

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

38752

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:

0.000144

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000128

AC:

168

AN:

1314122

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

639508

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:

0.0000153

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000158

Gnomad4 OTH exome

AF:

0.0000554

GnomAD4 genome

AF:

0.000105

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.000220

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.000101

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Nov 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.125C>A (p.T42N) alteration is located in exon 1 (coding exon 1) of the CLDN5 gene. This alteration results from a C to A substitution at nucleotide position 125, causing the threonine (T) at amino acid position 42 to be replaced by an asparagine (N). 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

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.51

CADD

Benign

2.2

DANN

Benign

0.82

DEOGEN2

Benign

0.0070

T;T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.23

.;.;T

M_CAP

Benign

0.045

MetaRNN

Benign

0.045

T;T;T

MetaSVM

Benign

-0.86

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.18

N;N;N

REVEL

Benign

0.21

Sift

Benign

0.11

T;T;T

Sift4G

Uncertain

0.0070

D;D;D

Polyphen

0.16

B;B;B

Vest4

0.051

MutPred

0.15

Loss of phosphorylation at T42 (P = 0.017);Loss of phosphorylation at T42 (P = 0.017);Loss of phosphorylation at T42 (P = 0.017);

MVP

0.47

MPC

1.7

ClinPred

0.077

GERP RS

-5.6

gMVP

0.062

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

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