22-19524078-C-CGGT

Variant names:

• chr22-19524078-C-CGGT
• NM_001363066.2:c.175_177dupACC

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4_Supporting PP5_Moderate

The NM_001363066.2(CLDN5):​c.175_177dupACC​(p.Thr59dup) variant causes a conservative inframe insertion 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLDN5 NM_001363066.2 conservative_inframe_insertion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -5.30

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 5 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.
• PP5: Variant 22-19524078-C-CGGT is Pathogenic according to our data. Variant chr22-19524078-C-CGGT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3067178.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN5	NM_001363066.2	c.175_177dupACC	p.Thr59dup	conservative_inframe_insertion	Exon 1 of 1	ENST00000618236.2	NP_001349995.1
CLDN5	NM_001130861.1	c.430_432dupACC	p.Thr144dup	conservative_inframe_insertion	Exon 1 of 1		NP_001124333.1
CLDN5	NM_001363067.2	c.430_432dupACC	p.Thr144dup	conservative_inframe_insertion	Exon 2 of 2		NP_001349996.1
CLDN5	NM_003277.4	c.430_432dupACC	p.Thr144dup	conservative_inframe_insertion	Exon 2 of 2		NP_003268.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN5	ENST00000618236.2	c.175_177dupACC	p.Thr59dup	conservative_inframe_insertion	Exon 1 of 1	6	NM_001363066.2	ENSP00000480623.1
CLDN5	ENST00000403084.1	c.430_432dupACC	p.Thr144dup	conservative_inframe_insertion	Exon 1 of 1	6		ENSP00000384554.1
CLDN5	ENST00000406028.1	c.430_432dupACC	p.Thr144dup	conservative_inframe_insertion	Exon 2 of 2	2		ENSP00000385477.1
CLDN5	ENST00000413119.2	c.430_432dupACC	p.Thr144dup	conservative_inframe_insertion	Exon 2 of 2	2		ENSP00000400612.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

CLDN5-related neurodevelopmental disorder Pathogenic:1

Feb 29, 2024

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Splicing

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: chr22-19511601;