chr5-69509251-A-C

Position:

• chr5-69509251-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001205254.2(OCLN):​c.161A>C​(p.His54Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: OCLN NM_001205254.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OCLN	NM_001205254.2	c.161A>C	p.His54Pro	missense_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.161A>C	p.His54Pro	missense_variant	3/9	1	NM_001205254.2	ENSP00000379719	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

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

Feb 03, 2022

The c.161A>C (p.H54P) alteration is located in exon 3 (coding exon 2) of the OCLN gene. This alteration results from a A to C substitution at nucleotide position 161, causing the histidine (H) at amino acid position 54 to be replaced by a proline (P). 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	Benign	0.18
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.72	.;T
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.9	D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.69		Gain of catalytic residue at H54 (P = 0.0231);Gain of catalytic residue at H54 (P = 0.0231);
MVP		0.95
MPC		0.33
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.84
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-68805078;