rs369518478

Positions:

• chr5-69534724-G-A
• chr5-69534724-G-C

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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

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 -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 [Likely_benign]. Clinvar id 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. gnomad4_exome 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 gnomad4_exome. There are 624 alleles in male gnomad4_exome subpopulation. Median coverage is 12. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OCLN	NM_001205254.2	c.922G>A	p.Val308Met	missense_variant	5/9	ENST00000396442.7	NP_001192183.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OCLN	ENST00000396442.7	c.922G>A	p.Val308Met	missense_variant	5/9	1	NM_001205254.2	ENSP00000379719	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 383 AN: 93456 Hom.: 2 Cov.: 11 FAILED QC

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

GnomAD3 exomes AF: 0.00220 AC: 500 AN: 226864 Hom.: 44 AF XY: 0.00231 AC XY: 285 AN XY: 123502

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 SAS exome AF: 0.00630

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

Gnomad4 AFR exome AF: 0.0198

Gnomad4 AMR exome AF: 0.00120

Gnomad4 ASJ exome AF: 0.000241

Gnomad4 EAS exome AF: 0.0000823

Gnomad4 SAS exome AF: 0.00618

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000111

Gnomad4 OTH exome AF: 0.00212

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

Gnomad4 AFR AF: 0.0179

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.000761

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00305

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000183

Gnomad4 OTH AF: 0.00767

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

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 12, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 20, 2016

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 v4.3

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;T;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.67	.;T;T
MetaRNN	Benign	0.0031	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.32	N;N;.
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.18	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.61	T;T;T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.0030	B;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

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

LitVar

Other links and lift over

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