rs145980033

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_014687.4(RUBCN):​c.593C>T​(p.Pro198Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000697 in 1,614,098 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0038 ( 6 hom., cov: 32)
Exomes 𝑓: 0.00037 ( 5 hom. )

Consequence

RUBCN
NM_014687.4 missense

Scores

3
15

Clinical Significance

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

Conservation

PhyloP100: 4.83
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.006392628).
BP6
Variant 3-197701842-G-A is Benign according to our data. Variant chr3-197701842-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 548452.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
BS2
High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RUBCNNM_014687.4 linkuse as main transcriptc.593C>T p.Pro198Leu missense_variant 6/20 ENST00000296343.10 NP_055502.1 Q92622-1Q8N4U6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RUBCNENST00000296343.10 linkuse as main transcriptc.593C>T p.Pro198Leu missense_variant 6/201 NM_014687.4 ENSP00000296343.5 Q92622-1

Frequencies

GnomAD3 genomes
AF:
0.00379
AC:
577
AN:
152114
Hom.:
5
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0131
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00144
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000770
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.000906
AC:
226
AN:
249442
Hom.:
1
AF XY:
0.000717
AC XY:
97
AN XY:
135348
show subpopulations
Gnomad AFR exome
AF:
0.0123
Gnomad AMR exome
AF:
0.000725
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000556
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000442
Gnomad OTH exome
AF:
0.000330
GnomAD4 exome
AF:
0.000369
AC:
539
AN:
1461866
Hom.:
5
Cov.:
32
AF XY:
0.000326
AC XY:
237
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.0128
Gnomad4 AMR exome
AF:
0.000715
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000428
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000180
Gnomad4 OTH exome
AF:
0.000629
GnomAD4 genome
AF:
0.00385
AC:
586
AN:
152232
Hom.:
6
Cov.:
32
AF XY:
0.00392
AC XY:
292
AN XY:
74428
show subpopulations
Gnomad4 AFR
AF:
0.0133
Gnomad4 AMR
AF:
0.00144
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000965
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00237
Alfa
AF:
0.000523
Hom.:
0
Bravo
AF:
0.00428
ESP6500AA
AF:
0.0117
AC:
45
ESP6500EA
AF:
0.000121
AC:
1
ExAC
AF:
0.00111
AC:
134
Asia WGS
AF:
0.00173
AC:
6
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Autosomal recessive spinocerebellar ataxia 15 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesMar 05, 2018- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 19, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
23
DANN
Benign
0.90
DEOGEN2
Benign
0.012
.;T;T
Eigen
Benign
0.084
Eigen_PC
Benign
0.21
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.88
D;D;D
MetaRNN
Benign
0.0064
T;T;T
MetaSVM
Benign
-0.65
T
MutationAssessor
Benign
1.7
.;L;.
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-2.4
N;N;N
REVEL
Benign
0.097
Sift
Benign
0.065
T;T;T
Sift4G
Benign
0.10
T;T;T
Polyphen
0.010
B;B;B
Vest4
0.45
MVP
0.34
MPC
0.38
ClinPred
0.016
T
GERP RS
5.9
Varity_R
0.057
gMVP
0.65

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs145980033; hg19: chr3-197428713; COSMIC: COSV99065980; COSMIC: COSV99065980; API