5-69509160-C-G

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.70C>G(p.Pro24Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0104 in 1,613,900 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (9 hom., cov: 33)
  • Exomes 𝑓: 0.011 (91 hom.)
• Consequence: OCLN NM_001205254.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.78

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=0.0089428425).
• BP6: Variant 5-69509160-C-G is Benign according to our data. Variant chr5-69509160-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 159462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00842 (1283/152306) while in subpopulation NFE AF= 0.0123 (835/68034). AF 95% confidence interval is 0.0116. There are 9 homozygotes in gnomad4. There are 633 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OCLN	NM_001205254.2	c.70C>G	p.Pro24Ala	missense_variant	3/9	ENST00000396442.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OCLN	ENST00000396442.7	c.70C>G	p.Pro24Ala	missense_variant	3/9	1	NM_001205254.2	P1

Frequencies

GnomAD3 genomes AF: 0.00843 AC: 1283 AN: 152188 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.0169

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00881 AC: 2214 AN: 251396 Hom.: 13 AF XY: 0.00832 AC XY: 1131 AN XY: 135886

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00703

Gnomad ASJ exome AF: 0.00625

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00196

Gnomad FIN exome AF: 0.0198

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.0106 AC: 15434 AN: 1461594 Hom.: 91 Cov.: 33 AF XY: 0.0102 AC XY: 7386 AN XY: 727130

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.00760

Gnomad4 ASJ exome AF: 0.00601

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00210

Gnomad4 FIN exome AF: 0.0213

Gnomad4 NFE exome AF: 0.0118

Gnomad4 OTH exome AF: 0.00801

GnomAD4 genome AF: 0.00842 AC: 1283 AN: 152306 Hom.: 9 Cov.: 33 AF XY: 0.00850 AC XY: 633 AN XY: 74474

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.0100

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00165

Gnomad4 FIN AF: 0.0169

Gnomad4 NFE AF: 0.0123

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0104 Hom.: 7

Bravo AF: 0.00707

TwinsUK AF: 0.0124 AC: 46

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0102 AC: 88

ExAC AF: 0.00853 AC: 1036

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00943

EpiControl AF: 0.00972

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 05, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	OCLN: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -

Pseudo-TORCH syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0089	T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.014	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.99	D;D
Vest4		0.57
MVP		0.94
MPC		0.36
ClinPred		0.014	T
GERP RS		6.0
Varity_R		0.10
gMVP		0.66

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: rs147125035; hg19: chr5-68804987; COSMIC: COSV99051151;