Genetic Variant OCLN:p.Val308Leu (chr5-69534724-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001205254.2(OCLN):c.922G>C(p.Val308Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V308M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.010 ( 7 hom., cov: 11)

Exomes 𝑓: 0.0015 ( 58 hom. )

Consequence

OCLN
NM_001205254.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.87

Publications

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

OCLN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020353496).

BP6

Variant 5-69534724-G-C is Benign according to our data. Variant chr5-69534724-G-C is described in ClinVar as Benign. ClinVar VariationId is 1283292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0102 (951/93458) while in subpopulation AFR AF = 0.0456 (884/19400). AF 95% confidence interval is 0.0431. There are 7 homozygotes in GnomAd4. There are 437 alleles in the male GnomAd4 subpopulation. Median coverage is 11. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

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	HGVSp	Effect	Exon Rank	Protein	UniProt
OCLN	NM_001205254.2	MANE Select	c.922G>C	p.Val308Leu	missense	Exon 5 of 9	NP_001192183.1	Q16625-1
OCLN	NM_001438604.1		c.922G>C	p.Val308Leu	missense	Exon 5 of 9	NP_001425533.1
OCLN	NM_002538.4		c.922G>C	p.Val308Leu	missense	Exon 5 of 9	NP_002529.1	Q16625-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OCLN	ENST00000396442.7	TSL:1 MANE Select	c.922G>C	p.Val308Leu	missense	Exon 5 of 9	ENSP00000379719.2	Q16625-1
OCLN	ENST00000355237.6	TSL:1	c.922G>C	p.Val308Leu	missense	Exon 5 of 9	ENSP00000347379.2	Q16625-1
OCLN	ENST00000538151.2	TSL:1	c.169G>C	p.Val57Leu	missense	Exon 3 of 7	ENSP00000445940.1	Q16625-4

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

943

AN:

93388

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0453

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00361

Gnomad ASJ

AF:

0.00533

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00373

Gnomad NFE

AF:

0.000183

Gnomad OTH

AF:

0.00955

GnomAD2 exomes

AF:

0.00361

AC:

820

AN:

226864

AF XY:

0.00308

show subpopulations

Gnomad AFR exome

AF:

0.0539

Gnomad AMR exome

AF:

0.00277

Gnomad ASJ exome

AF:

0.00528

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000186

Gnomad OTH exome

AF:

0.00216

GnomAD4 exome

AF:

0.00153

AC:

1270

AN:

828788

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

582

AN XY:

431272

show subpopulations

African (AFR)

AF:

0.0491

AC:

858

AN:

17468

American (AMR)

AF:

0.00257

AC:

105

AN:

40922

Ashkenazi Jewish (ASJ)

AF:

0.00391

AC:

AN:

20706

East Asian (EAS)

AF:

0.00

AC:

AN:

36442

South Asian (SAS)

AF:

0.000156

AC:

AN:

70552

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51060

Middle Eastern (MID)

AF:

0.000952

AC:

AN:

3152

European-Non Finnish (NFE)

AF:

0.000155

AC:

AN:

549872

Other (OTH)

AF:

0.00329

AC:

127

AN:

38614

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

123

164

205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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

AF:

0.0102

AC:

951

AN:

93458

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

437

AN XY:

43328

show subpopulations

African (AFR)

AF:

0.0456

AC:

884

AN:

19400

American (AMR)

AF:

0.00361

AC:

AN:

8870

Ashkenazi Jewish (ASJ)

AF:

0.00533

AC:

AN:

2628

East Asian (EAS)

AF:

0.00

AC:

AN:

3528

South Asian (SAS)

AF:

0.00

AC:

AN:

2292

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5600

Middle Eastern (MID)

AF:

0.00407

AC:

AN:

246

European-Non Finnish (NFE)

AF:

0.000184

AC:

AN:

49046

Other (OTH)

AF:

0.00937

AC:

AN:

1174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

106

141

176

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00211

Hom.:

ESP6500AA

AF:

0.0522

AC:

177

ESP6500EA

AF:

0.000247

AC:

ExAC

AF:

0.00532

AC:

630

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.062

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0020

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.7

PhyloP100

1.9

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.070

REVEL

Benign

0.14

Sift

Benign

0.90

Sift4G

Benign

0.88

Polyphen

0.0070

Vest4

0.23

MutPred

0.12

Gain of glycosylation at P311 (P = 0.105)

MVP

0.59

MPC

1.9

ClinPred

0.0016

GERP RS

1.8

Varity_R

0.040

gMVP

0.28

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over