rs587777235

Variant names:

• chr3-197676906-AG-A
• rs587777235
• NM_014687.4:c.2624delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_014687.4(RUBCN):​c.2624delC​(p.Ala875ValfsTer146) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RUBCN NM_014687.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.55
• Publications: 3 publications found

Genes affected

RUBCN (HGNC:28991): (rubicon autophagy regulator) The protein encoded by this gene is a negative regulator of autophagy and endocytic trafficking and controls endosome maturation. This protein contains two conserved domains, an N-terminal RUN domain and a C-terminal DUF4206 domain. The RUN domain is involved in Ras-like GTPase signaling, and the DUF4206 domain contains a diacylglycerol (DAG) binding-like motif. Mutation in this gene results in deletion of the DAG binding-like motif and causes a recessive ataxia. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Apr 2014]

RUBCN Gene-Disease associations (from GenCC):

• autosomal recessive spinocerebellar ataxia 15

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, PanelApp Australia, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-197676906-AG-A is Pathogenic according to our data. Variant chr3-197676906-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 120216.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014687.4. 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
	RUBCN	NM_014687.4	MANE Select	c.2624delC	p.Ala875ValfsTer146	frameshift	Exon 18 of 20	NP_055502.1	Q92622-1
	RUBCN	NM_001346873.2		c.2741delC	p.Ala914ValfsTer146	frameshift	Exon 20 of 22	NP_001333802.1	A0A9L9PY84
	RUBCN	NM_001145642.5		c.2489delC	p.Ala830ValfsTer146	frameshift	Exon 19 of 21	NP_001139114.1	Q92622-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUBCN	ENST00000296343.10	TSL:1 MANE Select	c.2624delC	p.Ala875ValfsTer146	frameshift	Exon 18 of 20	ENSP00000296343.5	Q92622-1
	RUBCN	ENST00000415452.5	TSL:1	c.1973delC	p.Ala658fs	frameshift	Exon 14 of 14	ENSP00000409618.1	H7C357
	RUBCN	ENST00000707076.1		c.2741delC	p.Ala914ValfsTer98	frameshift	Exon 20 of 22	ENSP00000516727.1	A0A9L9PY84

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Autosomal recessive spinocerebellar ataxia 15 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.5
Mutation Taster		=8/192	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs587777235; hg19: chr3-197403777;