rs35107257

Positions:

• chr5-69509789-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001205254.2(OCLN):​c.699G>A​(p.Leu233=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0347 in 1,613,784 control chromosomes in the GnomAD database, including 1,166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (63 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1103 hom.)
• Consequence: OCLN NM_001205254.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.28

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 5-69509789-G-A is Benign according to our data. Variant chr5-69509789-G-A is described in ClinVar as [Benign]. Clinvar id is 138568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-69509789-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.28 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.026 (3957/152210) while in subpopulation NFE AF= 0.0382 (2598/68008). AF 95% confidence interval is 0.037. There are 63 homozygotes in gnomad4. There are 1930 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 63 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OCLN	NM_001205254.2	c.699G>A	p.Leu233=	synonymous_variant	3/9	ENST00000396442.7	NP_001192183.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OCLN	ENST00000396442.7	c.699G>A	p.Leu233=	synonymous_variant	3/9	1	NM_001205254.2	ENSP00000379719	P1

Frequencies

GnomAD3 genomes AF: 0.0260 AC: 3958 AN: 152092 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.00681

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0463

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0382

Gnomad OTH AF: 0.0296

GnomAD3 exomes AF: 0.0233 AC: 5823 AN: 250322 Hom.: 95 AF XY: 0.0227 AC XY: 3070 AN XY: 135314

Gnomad AFR exome AF: 0.00665

Gnomad AMR exome AF: 0.0158

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00565

Gnomad FIN exome AF: 0.0395

Gnomad NFE exome AF: 0.0342

Gnomad OTH exome AF: 0.0279

GnomAD4 exome AF: 0.0356 AC: 51967 AN: 1461574 Hom.: 1103 Cov.: 34 AF XY: 0.0345 AC XY: 25119 AN XY: 727102

Gnomad4 AFR exome AF: 0.00570

Gnomad4 AMR exome AF: 0.0155

Gnomad4 ASJ exome AF: 0.0125

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00565

Gnomad4 FIN exome AF: 0.0398

Gnomad4 NFE exome AF: 0.0414

Gnomad4 OTH exome AF: 0.0334

GnomAD4 genome AF: 0.0260 AC: 3957 AN: 152210 Hom.: 63 Cov.: 32 AF XY: 0.0259 AC XY: 1930 AN XY: 74414

Gnomad4 AFR AF: 0.00679

Gnomad4 AMR AF: 0.0240

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.0463

Gnomad4 NFE AF: 0.0382

Gnomad4 OTH AF: 0.0293

Alfa AF: 0.0316 Hom.: 41

Bravo AF: 0.0246

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0330

EpiControl AF: 0.0347

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 18, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.3
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs35107257; hg19: chr5-68805616;