22-19524397-CTC-TT

Variant names:

• chr22-19524397-CTC-TT
• NM_001363066.2:c.-144_-142delGAGinsAA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_003277.4(CLDN5):​c.112_114delGAGinsAA​(p.Glu38LysfsTer47) variant causes a frameshift, synonymous change involving the alteration of a non-conserved nucleotide. 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_003277.4 frameshift, synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0950
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003277.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN5	NM_001363066.2	MANE Select	c.-144_-142delGAGinsAA		5_prime_UTR	Exon 1 of 1	NP_001349995.1	O00501
	CLDN5	NM_001130861.1		c.112_114delGAGinsAA	p.Glu38LysfsTer47	frameshift synonymous	Exon 1 of 1	NP_001124333.1	O00501
	CLDN5	NM_001363067.2		c.112_114delGAGinsAA	p.Glu38LysfsTer47	frameshift synonymous	Exon 2 of 2	NP_001349996.1	D3DX19

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN5	ENST00000618236.2	TSL:6 MANE Select	c.-144_-142delGAGinsAA		5_prime_UTR	Exon 1 of 1	ENSP00000480623.1	O00501
	CLDN5	ENST00000403084.1	TSL:6	c.112_114delGAGinsAA	p.Glu38LysfsTer47	frameshift synonymous	Exon 1 of 1	ENSP00000384554.1	D3DX19
	CLDN5	ENST00000406028.1	TSL:2	c.112_114delGAGinsAA	p.Glu38LysfsTer47	frameshift synonymous	Exon 2 of 2	ENSP00000385477.1	D3DX19

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.095

Splicing

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

Other links and lift over

hg19: chr22-19511920;