NM_001205254.2:c.1004G>T

Variant names:

• chr5-69534806-G-T
• rs201673353
• NM_001205254.2:c.1004G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001205254.2(OCLN):​c.1004G>T​(p.Arg335Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R335Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 18)
  • Exomes 𝑓: 0.0000016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OCLN NM_001205254.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.822
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10387504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OCLN	NM_001205254.2	c.1004G>T	p.Arg335Leu	missense_variant	Exon 5 of 9	ENST00000396442.7	NP_001192183.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OCLN	ENST00000396442.7	c.1004G>T	p.Arg335Leu	missense_variant	Exon 5 of 9	1	NM_001205254.2	ENSP00000379719.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 123556 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000160 AC: 2 AN: 1246844 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 628336

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23126

American (AMR) AF: 0.00 AC: 0 AN: 43040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23788

East Asian (EAS) AF: 0.00 AC: 0 AN: 38834

South Asian (SAS) AF: 0.00 AC: 0 AN: 80662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4700

European-Non Finnish (NFE) AF: 0.00000215 AC: 2 AN: 928110

Other (OTH) AF: 0.00 AC: 0 AN: 52428

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000081), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 123556 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 59278

African (AFR) AF: 0.00 AC: 0 AN: 26466

American (AMR) AF: 0.00 AC: 0 AN: 12684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3146

East Asian (EAS) AF: 0.00 AC: 0 AN: 4566

South Asian (SAS) AF: 0.00 AC: 0 AN: 3676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 61866

Other (OTH) AF: 0.00 AC: 0 AN: 1668

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	0.0083	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.81	.;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.8	L;L;.
PhyloP100		0.82
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.68	N;N;N
REVEL	Benign	0.19
Sift	Uncertain	0.023	D;D;T
Sift4G	Benign	0.45	T;T;T
Polyphen		0.0050	B;B;.
Vest4		0.34
MutPred		0.29		Loss of methylation at K334 (P = 0.065);Loss of methylation at K334 (P = 0.065);.;
MVP		0.72
MPC		2.4
ClinPred		0.22	T
GERP RS		2.1
Varity_R		0.072
gMVP		0.50
Mutation Taster		=84/16	polymorphism

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: rs201673353; hg19: chr5-68830633;