rs1029605974

Variant names:

• chr5-69509133-C-A
• rs1029605974
• NM_001205254.2:c.51-8C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-69509133-C-A
• chr5-69509133-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001205254.2(OCLN):​c.51-8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: OCLN NM_001205254.2 splice_region, intron
• Scores: Splicing: ADA: 0.0009549
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.991
• Publications: 0 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 5-69509133-C-A is Benign according to our data. Variant chr5-69509133-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1674076.Status of the report is criteria_provided_single_submitter, 1 stars.

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.51-8C>A		splice_region intron	N/A	NP_001192183.1	Q16625-1
	OCLN	NM_001438604.1		c.51-8C>A		splice_region intron	N/A	NP_001425533.1
	OCLN	NM_002538.4		c.51-8C>A		splice_region intron	N/A	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.51-8C>A		splice_region intron	N/A	ENSP00000379719.2	Q16625-1
	OCLN	ENST00000355237.6	TSL:1	c.51-8C>A		splice_region intron	N/A	ENSP00000347379.2	Q16625-1
	OCLN	ENST00000538151.2	TSL:1	c.-24-4815C>A		intron	N/A	ENSP00000445940.1	Q16625-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 250968 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000163

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459330 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726174

⚠️ 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: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109736

Other (OTH) AF: 0.00 AC: 0 AN: 60294

⚠️ 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 Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.1
DANN	Benign	0.81
PhyloP100		-0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00095
dbscSNV1_RF	Benign	0.076
SpliceAI score (max)		0.010		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: rs1029605974; hg19: chr5-68804960;