3-197681130-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_014687.4(RUBCN):c.2429G>A(p.Arg810Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000941 in 1,608,634 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00083 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00095 ( 1 hom. )

Consequence

RUBCN
NM_014687.4 missense, splice_region

Scores

Splicing: ADA: 0.9495

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 4.96

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.023369938).

BP6

Variant 3-197681130-C-T is Benign according to our data. Variant chr3-197681130-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2397886.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}. Variant chr3-197681130-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUBCN	NM_014687.4 linkuse as main transcript	c.2429G>A	p.Arg810Gln	missense_variant, splice_region_variant	16/20	ENST00000296343.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUBCN	ENST00000296343.10 linkuse as main transcript	c.2429G>A	p.Arg810Gln	missense_variant, splice_region_variant	16/20	1	NM_014687.4	P1	Q92622-1

Frequencies

GnomAD3 genomes

AF:

0.000829

AC:

126

AN:

151910

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.000394

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.000822

AC:

205

AN:

249474

Hom.:

AF XY:

0.000887

AC XY:

120

AN XY:

135350

show subpopulations

Gnomad AFR exome

AF:

0.000388

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00153

Gnomad NFE exome

AF:

0.00137

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000953

AC:

1388

AN:

1456606

Hom.:

Cov.:

AF XY:

0.000943

AC XY:

684

AN XY:

724978

show subpopulations

Gnomad4 AFR exome

AF:

0.000240

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00174

Gnomad4 NFE exome

AF:

0.00108

Gnomad4 OTH exome

AF:

0.00106

GnomAD4 genome

AF:

0.000829

AC:

126

AN:

152028

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.00129

Gnomad4 OTH

AF:

0.00333

Alfa

AF:

0.000958

Hom.:

Bravo

AF:

0.000691

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000503

AC:

ESP6500EA

AF:

0.000720

AC:

ExAC

AF:

0.000753

AC:

EpiCase

AF:

0.00147

EpiControl

AF:

0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	RUBCN: BP4 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2022

The c.2294G>A (p.R765Q) alteration is located in exon 17 (coding exon 16) of the RUBCN gene. This alteration results from a G to A substitution at nucleotide position 2294, causing the arginine (R) at amino acid position 765 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.21

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.043

MetaRNN

Benign

0.023

T;T

MetaSVM

Benign

-0.31

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.9

D;D

REVEL

Benign

0.077

Sift

Uncertain

0.010

D;D

Sift4G

Uncertain

0.052

T;T

Polyphen

0.33

B;P

Vest4

0.37

MVP

0.43

MPC

1.1

ClinPred

0.069

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.45

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.95

dbscSNV1_RF

Benign

0.62

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over