22-19524014-C-T

Variant names:

• chr22-19524014-C-T
• NM_001363066.2:c.242G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001363066.2(CLDN5):​c.242G>A​(p.Arg81Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLDN5 NM_001363066.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.99

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN5	NM_001363066.2	c.242G>A	p.Arg81Gln	missense_variant	Exon 1 of 1	ENST00000618236.2	NP_001349995.1
CLDN5	NM_001130861.1	c.497G>A	p.Arg166Gln	missense_variant	Exon 1 of 1		NP_001124333.1
CLDN5	NM_001363067.2	c.497G>A	p.Arg166Gln	missense_variant	Exon 2 of 2		NP_001349996.1
CLDN5	NM_003277.4	c.497G>A	p.Arg166Gln	missense_variant	Exon 2 of 2		NP_003268.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN5	ENST00000618236.2	c.242G>A	p.Arg81Gln	missense_variant	Exon 1 of 1	6	NM_001363066.2	ENSP00000480623.1
CLDN5	ENST00000403084.1	c.497G>A	p.Arg166Gln	missense_variant	Exon 1 of 1	6		ENSP00000384554.1
CLDN5	ENST00000406028.1	c.497G>A	p.Arg166Gln	missense_variant	Exon 2 of 2	2		ENSP00000385477.1
CLDN5	ENST00000413119.2	c.497G>A	p.Arg166Gln	missense_variant	Exon 2 of 2	2		ENSP00000400612.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Sep 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.497G>A (p.R166Q) alteration is located in exon 1 (coding exon 1) of the CLDN5 gene. This alteration results from a G to A substitution at nucleotide position 497, causing the arginine (R) at amino acid position 166 to be replaced by a glutamine (Q). 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
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D;D;D;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	.;D;.;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.1	.;M;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.0	D;.;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.62
MutPred		0.84		Gain of catalytic residue at R166 (P = 0.0458);.;Gain of catalytic residue at R166 (P = 0.0458);Gain of catalytic residue at R166 (P = 0.0458);
MVP		0.94
MPC		2.4
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.54
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-19511537; COSMIC: COSV54244034; COSMIC: COSV54244034;