chr5-69509160-C-G

Variant names:

• chr5-69509160-C-G
• rs147125035
• NM_001205254.2:c.70C>G

Variant summary

Our verdict is Benign. The variant received -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:6
• Conservation: PhyloP100: 4.78
• Publications: 13 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• pseudo-TORCH syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

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.70C>G	p.Pro24Ala	missense	Exon 3 of 9	NP_001192183.1	Q16625-1
	OCLN	NM_001438604.1		c.70C>G	p.Pro24Ala	missense	Exon 3 of 9	NP_001425533.1
	OCLN	NM_002538.4		c.70C>G	p.Pro24Ala	missense	Exon 3 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.70C>G	p.Pro24Ala	missense	Exon 3 of 9	ENSP00000379719.2	Q16625-1
	OCLN	ENST00000355237.6	TSL:1	c.70C>G	p.Pro24Ala	missense	Exon 3 of 9	ENSP00000347379.2	Q16625-1
	OCLN	ENST00000538151.2	TSL:1	c.-24-4788C>G		intron	N/A	ENSP00000445940.1	Q16625-4

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

GnomAD2 exomes AF: 0.00881 AC: 2214 AN: 251396 AF XY: 0.00832

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 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

African (AFR) AF: 0.00158 AC: 53 AN: 33478

American (AMR) AF: 0.00760 AC: 340 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00601 AC: 157 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00210 AC: 181 AN: 86250

European-Finnish (FIN) AF: 0.0213 AC: 1140 AN: 53398

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.0118 AC: 13065 AN: 1111750

Other (OTH) AF: 0.00801 AC: 484 AN: 60394

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

African (AFR) AF: 0.00147 AC: 61 AN: 41550

American (AMR) AF: 0.0100 AC: 153 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00165 AC: 8 AN: 4834

European-Finnish (FIN) AF: 0.0169 AC: 179 AN: 10608

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0123 AC: 835 AN: 68034

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Pseudo-TORCH syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0089	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.014	D
Polyphen		0.99	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
Mutation Taster		=83/17	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: rs147125035; hg19: chr5-68804987; COSMIC: COSV99051151;