22-19523788-C-A

Variant names:

• chr22-19523788-C-A
• NM_001363066.2:c.468G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001363066.2(CLDN5):​c.468G>T​(p.Gln156His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,454,012 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CLDN5 NM_001363066.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN5	NM_001363066.2	c.468G>T	p.Gln156His	missense_variant	Exon 1 of 1	ENST00000618236.2	NP_001349995.1
CLDN5	NM_001130861.1	c.723G>T	p.Gln241His	missense_variant	Exon 1 of 1		NP_001124333.1
CLDN5	NM_001363067.2	c.723G>T	p.Gln241His	missense_variant	Exon 2 of 2		NP_001349996.1
CLDN5	NM_003277.4	c.723G>T	p.Gln241His	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.468G>T	p.Gln156His	missense_variant	Exon 1 of 1	6	NM_001363066.2	ENSP00000480623.1
CLDN5	ENST00000403084.1	c.723G>T	p.Gln241His	missense_variant	Exon 1 of 1	6		ENSP00000384554.1
CLDN5	ENST00000406028.1	c.723G>T	p.Gln241His	missense_variant	Exon 2 of 2	2		ENSP00000385477.1
CLDN5	ENST00000413119.2	c.723G>T	p.Gln241His	missense_variant	Exon 2 of 2	2		ENSP00000400612.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1454012 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722814

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 18, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;D;D;D
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.30	.;T;.;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.4	.;M;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-4.2	D;.;D;D
REVEL	Uncertain	0.64
Sift	Benign	0.048	D;.;D;D
Sift4G	Uncertain	0.049	D;T;D;D
Polyphen		0.90	P;.;P;P
Vest4		0.23
MutPred		0.56		Loss of catalytic residue at Q241 (P = 0.0848);.;Loss of catalytic residue at Q241 (P = 0.0848);Loss of catalytic residue at Q241 (P = 0.0848);
MVP		0.69
MPC		1.6
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.24
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr22-19511311;