rs35107257

Variant names:

• chr5-69509789-G-A
• rs35107257
• NM_001205254.2:c.699G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001205254.2(OCLN):​c.699G>A​(p.Leu233Leu) 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
• Publications: 10 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: Benign. The variant received -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 VariationId is 138568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 63 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCLN	NM_001205254.2	MANE Select	c.699G>A	p.Leu233Leu	synonymous	Exon 3 of 9	NP_001192183.1	Q16625-1
	OCLN	NM_001438604.1		c.699G>A	p.Leu233Leu	synonymous	Exon 3 of 9	NP_001425533.1
	OCLN	NM_002538.4		c.699G>A	p.Leu233Leu	synonymous	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.699G>A	p.Leu233Leu	synonymous	Exon 3 of 9	ENSP00000379719.2	Q16625-1
	OCLN	ENST00000355237.6	TSL:1	c.699G>A	p.Leu233Leu	synonymous	Exon 3 of 9	ENSP00000347379.2	Q16625-1
	OCLN	ENST00000538151.2	TSL:1	c.-24-4159G>A		intron	N/A	ENSP00000445940.1	Q16625-4

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

GnomAD2 exomes AF: 0.0233 AC: 5823 AN: 250322 AF XY: 0.0227

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 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

African (AFR) AF: 0.00570 AC: 191 AN: 33480

American (AMR) AF: 0.0155 AC: 691 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0125 AC: 326 AN: 26134

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.00565 AC: 487 AN: 86256

European-Finnish (FIN) AF: 0.0398 AC: 2118 AN: 53262

Middle Eastern (MID) AF: 0.00850 AC: 49 AN: 5768

European-Non Finnish (NFE) AF: 0.0414 AC: 46084 AN: 1111858

Other (OTH) AF: 0.0334 AC: 2016 AN: 60394

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

African (AFR) AF: 0.00679 AC: 282 AN: 41532

American (AMR) AF: 0.0240 AC: 367 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4826

European-Finnish (FIN) AF: 0.0463 AC: 490 AN: 10590

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0382 AC: 2598 AN: 68008

Other (OTH) AF: 0.0293 AC: 62 AN: 2116

Alfa AF: 0.0336 Hom.: 178

Bravo AF: 0.0246

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0330

EpiControl AF: 0.0347

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.3
DANN	Benign	0.59
PhyloP100		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35107257; hg19: chr5-68805616;