dbSNP rs765505732: CLDN5:p.Gly31Arg (chr22-19524420-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The NM_003277.4(CLDN5):c.91G>C(p.Gly31Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G31S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CLDN5
NM_003277.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.044280797).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN5	NM_001130861.1 link	c.91G>C	p.Gly31Arg	missense_variant	Exon 1 of 1		NP_001124333.1	O00501D3DX19
CLDN5	NM_001363067.2 link	c.91G>C	p.Gly31Arg	missense_variant	Exon 2 of 2		NP_001349996.1
CLDN5	NM_003277.4 link	c.91G>C	p.Gly31Arg	missense_variant	Exon 2 of 2		NP_003268.2	O00501D3DX19
CLDN5	NM_001363066.2 link	c.-165G>C		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>C	p.Gly31Arg	missense_variant	Exon 1 of 1	6		ENSP00000384554.1	D3DX19
CLDN5	ENST00000406028.1 link	c.91G>C	p.Gly31Arg	missense_variant	Exon 2 of 2	2		ENSP00000385477.1	D3DX19
CLDN5	ENST00000413119.2 link	c.91G>C	p.Gly31Arg	missense_variant	Exon 2 of 2	2		ENSP00000400612.2	D3DX19
CLDN5	ENST00000618236.2 link	c.-165G>C		upstream_gene_variant		6	NM_001363066.2	ENSP00000480623.1	O00501

Frequencies

GnomAD3 genomes

AF:

0.00000657

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1294334

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

628172

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.00

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

1.3

DANN

Benign

0.53

DEOGEN2

Benign

0.0053

T;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.31

.;.;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.044

T;T;T

MetaSVM

Benign

-0.74

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.26

N;N;N

REVEL

Benign

0.23

Sift

Benign

0.54

T;T;T

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.0010

B;B;B

Vest4

0.13

MutPred

0.13

Gain of MoRF binding (P = 0.0183);Gain of MoRF binding (P = 0.0183);Gain of MoRF binding (P = 0.0183);

MVP

0.26

MPC

1.2

ClinPred

0.064

GERP RS

-10

gMVP

0.098

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over