NM_001205254.2:c.1004G>A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001205254.2(OCLN):​c.1004G>A​(p.Arg335Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 18)
  • Exomes 𝑓: 0.00016 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: OCLN NM_001205254.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pseudo-TORCH syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047424734).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001205254.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCLN	NM_001205254.2	MANE Select	c.1004G>A	p.Arg335Gln	missense	Exon 5 of 9	NP_001192183.1	Q16625-1
	OCLN	NM_001438604.1		c.1004G>A	p.Arg335Gln	missense	Exon 5 of 9	NP_001425533.1
	OCLN	NM_002538.4		c.1004G>A	p.Arg335Gln	missense	Exon 5 of 9	NP_002529.1	Q16625-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCLN	ENST00000396442.7	TSL:1 MANE Select	c.1004G>A	p.Arg335Gln	missense	Exon 5 of 9	ENSP00000379719.2	Q16625-1
	OCLN	ENST00000355237.6	TSL:1	c.1004G>A	p.Arg335Gln	missense	Exon 5 of 9	ENSP00000347379.2	Q16625-1
	OCLN	ENST00000538151.2	TSL:1	c.251G>A	p.Arg84Gln	missense	Exon 3 of 7	ENSP00000445940.1	Q16625-4

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 165 AN: 123338 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.00583

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000552

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00357

Gnomad NFE AF: 0.0000485

Gnomad OTH AF: 0.000600

GnomAD2 exomes AF: 0.000263 AC: 63 AN: 239548 AF XY: 0.000230

Gnomad AFR exome AF: 0.00456

Gnomad AMR exome AF: 0.0000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000160 AC: 199 AN: 1246484 Hom.: 1 Cov.: 19 AF XY: 0.000126 AC XY: 79 AN XY: 628184

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

African (AFR) AF: 0.00652 AC: 149 AN: 22862

American (AMR) AF: 0.000279 AC: 12 AN: 43004

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

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38834

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80660

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

Middle Eastern (MID) AF: 0.000426 AC: 2 AN: 4700

European-Non Finnish (NFE) AF: 0.0000162 AC: 15 AN: 928100

Other (OTH) AF: 0.000363 AC: 19 AN: 52380

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00135 AC: 167 AN: 123410 Hom.: 0 Cov.: 18 AF XY: 0.00116 AC XY: 69 AN XY: 59284

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

African (AFR) AF: 0.00588 AC: 155 AN: 26342

American (AMR) AF: 0.000552 AC: 7 AN: 12684

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4556

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

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

Middle Eastern (MID) AF: 0.00385 AC: 1 AN: 260

European-Non Finnish (NFE) AF: 0.0000485 AC: 3 AN: 61852

Other (OTH) AF: 0.000592 AC: 1 AN: 1690

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00270 Hom.: 1

ExAC AF: 0.000250 AC: 30

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.088	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.82
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.042
Sift	Benign	0.32	T
Sift4G	Benign	0.78	T
Polyphen		0.0010	B
Vest4		0.13
MVP		0.70
MPC		2.1
ClinPred		0.012	T
GERP RS		2.1
Varity_R		0.031
gMVP		0.36
Mutation Taster		=96/4	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; COSMIC: COSV62285575; COSMIC: COSV62285575;