rs730882227

Variant names:

• chr5-69509603-C-CT
• rs730882227
• NM_001205254.2:c.514dupT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001205254.2(OCLN):​c.514dupT​(p.Tyr172LeufsTer104) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: OCLN NM_001205254.2 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.97
• Publications: 0 publications found

Genes affected

OCLN (HGNC:8104): (occludin) This gene encodes an integral membrane protein that is required for cytokine-induced regulation of the tight junction paracellular permeability barrier. Mutations in this gene are thought to be a cause of band-like calcification with simplified gyration and polymicrogyria (BLC-PMG), an autosomal recessive neurologic disorder that is also known as pseudo-TORCH syndrome. Alternative splicing results in multiple transcript variants. A related pseudogene is present 1.5 Mb downstream on the q arm of chromosome 5. [provided by RefSeq, Apr 2011]

OCLN Gene-Disease associations (from GenCC):

• pseudo-TORCH syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pseudo-TORCH syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001205254.2. 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
	OCLN	NM_001205254.2	MANE Select	c.514dupT	p.Tyr172LeufsTer104	frameshift	Exon 3 of 9	NP_001192183.1	Q16625-1
	OCLN	NM_001438604.1		c.514dupT	p.Tyr172LeufsTer104	frameshift	Exon 3 of 9	NP_001425533.1
	OCLN	NM_002538.4		c.514dupT	p.Tyr172LeufsTer104	frameshift	Exon 3 of 9	NP_002529.1	Q16625-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCLN	ENST00000396442.7	TSL:1 MANE Select	c.514dupT	p.Tyr172LeufsTer104	frameshift	Exon 3 of 9	ENSP00000379719.2	Q16625-1
	OCLN	ENST00000355237.6	TSL:1	c.514dupT	p.Tyr172LeufsTer104	frameshift	Exon 3 of 9	ENSP00000347379.2	Q16625-1
	OCLN	ENST00000538151.2	TSL:1	c.-24-4344dupT		intron	N/A	ENSP00000445940.1	Q16625-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Cerebral calcification;C0557874:Global developmental delay;C2677180:Primary microcephaly (1)
-	1	-	Pseudo-TORCH syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs730882227; hg19: chr5-68805430;