chr5-69504175-A-G

Variant names:

• chr5-69504175-A-G
• rs1561331778
• NM_001205254.2:c.-68-2A>G

Variant summary

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

The NM_001205254.2(OCLN):​c.-68-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OCLN NM_001205254.2 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.39
• 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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• pseudo-TORCH syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000249295 (HGNC:):

ACMG classification

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

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• 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.-68-2A>G		splice_acceptor intron	N/A	NP_001192183.1	Q16625-1
	OCLN	NM_001438604.1		c.-68-2A>G		splice_acceptor intron	N/A	NP_001425533.1
	OCLN	NM_002538.4		c.-68-2A>G		splice_acceptor intron	N/A	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.-68-2A>G		splice_acceptor intron	N/A	ENSP00000379719.2	Q16625-1
	OCLN	ENST00000355237.6	TSL:1	c.-68-2A>G		splice_acceptor intron	N/A	ENSP00000347379.2	Q16625-1
	OCLN	ENST00000680027.1		c.-68-2A>G		splice_acceptor intron	N/A	ENSP00000506162.1	Q16625-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 886278 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 464828

African (AFR) AF: 0.00 AC: 0 AN: 22354

American (AMR) AF: 0.00 AC: 0 AN: 43802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22566

East Asian (EAS) AF: 0.00 AC: 0 AN: 37110

South Asian (SAS) AF: 0.00 AC: 0 AN: 74126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 587154

Other (OTH) AF: 0.00 AC: 0 AN: 41380

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	31
DANN	Benign	0.96
PhyloP100		1.4
PromoterAI		0.050	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.79
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.57		Position offset: 20
DS_AL_spliceai		1.0		Position offset: 2

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

Other links and lift over

dbSNP: rs1561331778; hg19: chr5-68800002;