22-19523831-ATGT-A

Variant names:

• chr22-19523831-ATGT-A
• NM_001363066.2:c.422_424delACA

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_001363066.2(CLDN5):​c.422_424delACA​(p.Asn141del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLDN5 NM_001363066.2 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.16

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
• PM4: Nonframeshift variant in NON repetitive region in NM_001363066.2. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN5	NM_001363066.2	c.422_424delACA	p.Asn141del	disruptive_inframe_deletion	Exon 1 of 1	ENST00000618236.2	NP_001349995.1
CLDN5	NM_001130861.1	c.677_679delACA	p.Asn226del	disruptive_inframe_deletion	Exon 1 of 1		NP_001124333.1
CLDN5	NM_001363067.2	c.677_679delACA	p.Asn226del	disruptive_inframe_deletion	Exon 2 of 2		NP_001349996.1
CLDN5	NM_003277.4	c.677_679delACA	p.Asn226del	disruptive_inframe_deletion	Exon 2 of 2		NP_003268.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN5	ENST00000618236.2	c.422_424delACA	p.Asn141del	disruptive_inframe_deletion	Exon 1 of 1	6	NM_001363066.2	ENSP00000480623.1
CLDN5	ENST00000403084.1	c.677_679delACA	p.Asn226del	disruptive_inframe_deletion	Exon 1 of 1	6		ENSP00000384554.1
CLDN5	ENST00000406028.1	c.677_679delACA	p.Asn226del	disruptive_inframe_deletion	Exon 2 of 2	2		ENSP00000385477.1
CLDN5	ENST00000413119.2	c.677_679delACA	p.Asn226del	disruptive_inframe_deletion	Exon 2 of 2	2		ENSP00000400612.2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Syndromic disease Uncertain:1

Sep 20, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0101 - Gain of function is a suggested mechanism of disease in this gene and is associated with CLDN5-related syndromic disease (MONDO:0002254). Over-expression of patient CLDN5 missense variants in a zebrafish model disrupts embryogenesis and impairs tight junction formation (PMID: 36477332). Additionally, transfected cell lines with the c.178G>A variant showed higher chloride ion permeability and lower sodium ion permeability when compared to wildtype, indicating anion-selective permeability (PMID: 35714222). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0216 - In-frame deletion in a non-repetitive region that has moderate conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated PMP22_Claudin domain (DECIPHER). (I) 0705 - No comparable in-frame variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

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: chr22-19511354;