NM_014687.4:c.2647-4C>G

Variant names:

• chr3-197675519-G-C
• rs368369578
• NM_014687.4:c.2647-4C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014687.4(RUBCN):​c.2647-4C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RUBCN NM_014687.4 splice_region, intron
• Scores: Splicing: ADA: 0.00004977
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.964

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUBCN	NM_014687.4	c.2647-4C>G		splice_region_variant, intron_variant	Intron 18 of 19	ENST00000296343.10	NP_055502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUBCN	ENST00000296343.10	c.2647-4C>G		splice_region_variant, intron_variant	Intron 18 of 19	1	NM_014687.4	ENSP00000296343.5
RUBCN	ENST00000707076.1	c.2764-4C>G		splice_region_variant, intron_variant	Intron 20 of 21			ENSP00000516727.1
RUBCN	ENST00000413360.5	c.2530-4C>G		splice_region_variant, intron_variant	Intron 17 of 18	5		ENSP00000405115.1
RUBCN	ENST00000273582.9	c.2512-4C>G		splice_region_variant, intron_variant	Intron 19 of 20	5		ENSP00000273582.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.5
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000050
dbscSNV1_RF	Benign	0.0040
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

Publications

LitVar

Other links and lift over

dbSNP: rs368369578; hg19: chr3-197402390;