5-69504256-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001205254.2(OCLN):c.12G>C(p.Arg4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: OCLN NM_001205254.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.862

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27157944).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OCLN	NM_001205254.2	c.12G>C	p.Arg4Ser	missense_variant	2/9	ENST00000396442.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OCLN	ENST00000396442.7	c.12G>C	p.Arg4Ser	missense_variant	2/9	1	NM_001205254.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457280 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 725342

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2022

The c.12G>C (p.R4S) alteration is located in exon 2 (coding exon 1) of the OCLN gene. This alteration results from a G to C substitution at nucleotide position 12, causing the arginine (R) at amino acid position 4 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.98	D;D
Vest4		0.27
MutPred		0.25		Gain of phosphorylation at R4 (P = 0.0019);Gain of phosphorylation at R4 (P = 0.0019);
MVP		0.85
MPC		0.38
ClinPred		0.87	D
GERP RS		1.9
Varity_R		0.31
gMVP		0.74

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: rs1032322032; hg19: chr5-68800083;