NM_014687.4:c.2623G>C

Variant names:

• chr3-197676908-C-G
• rs183738683
• NM_014687.4:c.2623G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014687.4(RUBCN):​c.2623G>C​(p.Ala875Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. A875T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RUBCN NM_014687.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.750
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37386513).

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.2623G>C	p.Ala875Pro	missense	Exon 18 of 20	NP_055502.1	Q92622-1
	RUBCN	NM_001346873.2		c.2740G>C	p.Ala914Pro	missense	Exon 20 of 22	NP_001333802.1	A0A9L9PY84
	RUBCN	NM_001145642.5		c.2488G>C	p.Ala830Pro	missense	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.2623G>C	p.Ala875Pro	missense	Exon 18 of 20	ENSP00000296343.5	Q92622-1
	RUBCN	ENST00000415452.5	TSL:1	c.1972G>C	p.Ala658Pro	missense	Exon 14 of 14	ENSP00000409618.1	H7C357
	RUBCN	ENST00000707076.1		c.2740G>C	p.Ala914Pro	missense	Exon 20 of 22	ENSP00000516727.1	A0A9L9PY84

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.050
Eigen_PC	Benign	-0.00082
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.75
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.12
Sift	Benign	0.14	T
Sift4G	Benign	0.13	T
Polyphen		0.13	B
Vest4		0.53
MutPred		0.44		Gain of glycosylation at T871 (P = 0.038)
MVP		0.46
MPC		0.84
ClinPred		0.68	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.79
Mutation Taster		=73/27	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: rs183738683; hg19: chr3-197403779;