NM_001205254.2:c.922G>A

Variant names:

• chr5-69534724-G-A
• rs369518478
• NM_001205254.2:c.922G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001205254.2(OCLN):​c.922G>A​(p.Val308Met) 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V308L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0041 (2 hom., cov: 11)
  • Exomes 𝑓: 0.0012 (31 hom.)
  • Failed GnomAD Quality Control
• Consequence: OCLN NM_001205254.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.87
• Publications: 6 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, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• pseudo-TORCH syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031420588).
• BP6: Variant 5-69534724-G-A is Benign according to our data. Variant chr5-69534724-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0012 (993/828788) while in subpopulation AFR AF = 0.0198 (347/17482). AF 95% confidence interval is 0.0181. There are 31 homozygotes in GnomAdExome4. There are 624 alleles in the male GnomAdExome4 subpopulation. Median coverage is 12. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 31 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCLN	NM_001205254.2	MANE Select	c.922G>A	p.Val308Met	missense	Exon 5 of 9	NP_001192183.1
	OCLN	NM_001438604.1		c.922G>A	p.Val308Met	missense	Exon 5 of 9	NP_001425533.1
	OCLN	NM_002538.4		c.922G>A	p.Val308Met	missense	Exon 5 of 9	NP_002529.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCLN	ENST00000396442.7	TSL:1 MANE Select	c.922G>A	p.Val308Met	missense	Exon 5 of 9	ENSP00000379719.2
	OCLN	ENST00000355237.6	TSL:1	c.922G>A	p.Val308Met	missense	Exon 5 of 9	ENSP00000347379.2
	OCLN	ENST00000538151.2	TSL:1	c.169G>A	p.Val57Met	missense	Exon 3 of 7	ENSP00000445940.1

Frequencies

GnomAD3 genomes AF: 0.00410 AC: 383 AN: 93456 Hom.: 2 Cov.: 11

Gnomad AFR AF: 0.0177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.000761

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00350

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000183

Gnomad OTH AF: 0.00781

GnomAD2 exomes AF: 0.00220 AC: 500 AN: 226864 AF XY: 0.00231

Gnomad AFR exome AF: 0.0216

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.000344

Gnomad EAS exome AF: 0.0000559

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000128

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00120 AC: 993 AN: 828788 Hom.: 31 Cov.: 12 AF XY: 0.00145 AC XY: 624 AN XY: 431272

African (AFR) AF: 0.0198 AC: 347 AN: 17482

American (AMR) AF: 0.00120 AC: 49 AN: 40928

Ashkenazi Jewish (ASJ) AF: 0.000241 AC: 5 AN: 20708

East Asian (EAS) AF: 0.0000823 AC: 3 AN: 36436

South Asian (SAS) AF: 0.00618 AC: 436 AN: 70550

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51060

Middle Eastern (MID) AF: 0.00317 AC: 10 AN: 3150

European-Non Finnish (NFE) AF: 0.000111 AC: 61 AN: 549860

Other (OTH) AF: 0.00212 AC: 82 AN: 38614

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00413 AC: 386 AN: 93528 Hom.: 2 Cov.: 11 AF XY: 0.00399 AC XY: 173 AN XY: 43362

African (AFR) AF: 0.0179 AC: 348 AN: 19468

American (AMR) AF: 0.00124 AC: 11 AN: 8870

Ashkenazi Jewish (ASJ) AF: 0.000761 AC: 2 AN: 2628

East Asian (EAS) AF: 0.00 AC: 0 AN: 3528

South Asian (SAS) AF: 0.00305 AC: 7 AN: 2292

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 246

European-Non Finnish (NFE) AF: 0.000183 AC: 9 AN: 49048

Other (OTH) AF: 0.00767 AC: 9 AN: 1174

Alfa AF: 0.000540 Hom.: 7

ExAC AF: 0.00308 AC: 365

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 12, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Jan 20, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.85
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.32	N
PhyloP100		1.9
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.12
Sift	Benign	0.61	T
Sift4G	Benign	0.34	T
Polyphen		0.0030	B
Vest4		0.18
MVP		0.59
MPC		1.9
ClinPred		0.0024	T
GERP RS		1.8
Varity_R		0.035
gMVP		0.27
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs369518478; hg19: chr5-68830551; COSMIC: COSV62285774;