Variant chr3-197701842-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000296343.10(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). Synonymous variant affecting the same amino acid position (i.e. P198P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0038 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 5 hom. )

Consequence

RUBCN
ENST00000296343.10 missense

Scores

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]

RUBCN links:

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: {Benign=1, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUBCN	NM_014687.4 linkuse as main transcript	c.593C>T	p.Pro198Leu	missense_variant	6/20	ENST00000296343.10	NP_055502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUBCN	ENST00000296343.10 linkuse as main transcript	c.593C>T	p.Pro198Leu	missense_variant	6/20	1	NM_014687.4	ENSP00000296343	P1	Q92622-1

Frequencies

GnomAD3 genomes

AF:

0.00379

AC:

577

AN:

152114

Hom.:

Cov.:

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.:

AF XY:

0.000717

AC XY:

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.:

Cov.:

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.:

Cov.:

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.:

Bravo

AF:

0.00428

ESP6500AA

AF:

0.0117

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.00111

AC:

134

Asia WGS

AF:

0.00173

AC:

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 submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.012

.;T;T

Eigen

Benign

0.084

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.88

D;D;D

MetaRNN

Benign

0.0064

T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.7

.;L;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.56

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

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.

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