Genetic Variant NM_001205254.2:c.1037+1G>T (chr5-69534840-G-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_001205254.2(OCLN):c.1037+1G>T variant causes a splice donor, intron change. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 19)

Exomes 𝑓: 0.000017 ( 1 hom. )

Consequence

OCLN
NM_001205254.2 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.56

Publications

1 publications found

Variant links:

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, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
pseudo-TORCH syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

OCLN links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 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.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
OCLN	NM_001205254.2	MANE Select	c.1037+1G>T	splice_donor intron	N/A	NP_001192183.1
OCLN	NM_001438604.1		c.1037+1G>T	splice_donor intron	N/A	NP_001425533.1
OCLN	NM_002538.4		c.1037+1G>T	splice_donor intron	N/A	NP_002529.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
OCLN	ENST00000396442.7	TSL:1 MANE Select	c.1037+1G>T	splice_donor intron	N/A	ENSP00000379719.2
OCLN	ENST00000355237.6	TSL:1	c.1037+1G>T	splice_donor intron	N/A	ENSP00000347379.2
OCLN	ENST00000538151.2	TSL:1	c.284+1G>T	splice_donor intron	N/A	ENSP00000445940.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000859

AC:

AN:

232714

AF XY:

0.00000790

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000186

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000168

AC:

AN:

1251482

Hom.:

Cov.:

AF XY:

0.0000222

AC XY:

AN XY:

629988

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22564

American (AMR)

AF:

0.00

AC:

AN:

35908

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22650

East Asian (EAS)

AF:

0.00

AC:

AN:

39036

South Asian (SAS)

AF:

0.00

AC:

AN:

77146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4964

European-Non Finnish (NFE)

AF:

0.0000222

AC:

AN:

945232

Other (OTH)

AF:

0.00

AC:

AN:

52394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000964

Hom.:

ExAC

AF:

0.00000835

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.61

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.87

PhyloP100

4.6

GERP RS

5.0

Mutation Taster

=1/99

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DL_spliceai

1.0

Position offset: -1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over