Variant 13-46368135-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_025113.5(RUBCNL):c.733C>G(p.Leu245Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

RUBCNL
NM_025113.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.332

Variant links:

Genes affected

RUBCNL (HGNC:20420): (rubicon like autophagy enhancer) This gene encodes a cysteine-rich protein that contains a putative zinc-RING and/or ribbon domain. The encoded protein is related to Run domain Beclin-1-interacting and cysteine-rich domain-containing protein, which plays a role in endocytic trafficking and autophagy. In cervical cancer cell lines, this gene is expressed at low levels and may function as a tumor suppressor. Promoter hypermethylation of this gene is observed in cervical cancer cell lines and tissue derived from human patients. [provided by RefSeq, Mar 2017]

RUBCNL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 (MetaRNN=0.017314047).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUBCNL	NM_025113.5 linkuse as main transcript	c.733C>G	p.Leu245Val	missense_variant	5/15	ENST00000429979.6	NP_079389.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUBCNL	ENST00000429979.6 linkuse as main transcript	c.733C>G	p.Leu245Val	missense_variant	5/15	5	NM_025113.5	ENSP00000396935	A2	Q9H714-5

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251158

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000465

AC:

AN:

1461668

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00188

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000180

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 2021

The c.733C>G (p.L245V) alteration is located in exon 5 (coding exon 3) of the RUBCNL gene. This alteration results from a C to G substitution at nucleotide position 733, causing the leucine (L) at amino acid position 245 to be replaced by a valine (V). 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

0.074

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.61

CADD

Benign

4.8

DANN

Benign

0.79

DEOGEN2

Benign

0.0054

.;.;T;T;.;.;.;.;T

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.62

T;T;T;.;T;T;.;T;T

M_CAP

Benign

0.0090

MetaRNN

Benign

0.017

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.78

.;.;N;N;N;N;N;.;N

REVEL

Benign

0.039

Sift

Benign

0.41

.;.;T;T;T;T;T;.;T

Sift4G

Benign

0.63

T;T;T;T;T;T;T;T;.

Polyphen

0.45, 0.70, 0.80, 0.95

.;P;P;P;P;P;P;.;.

Vest4

0.10

MutPred

0.14

.;.;Gain of glycosylation at S242 (P = 0.0853);Gain of glycosylation at S242 (P = 0.0853);.;Gain of glycosylation at S242 (P = 0.0853);.;.;.;

MVP

0.11

MPC

0.050

ClinPred

0.030

GERP RS

1.3

Varity_R

0.034

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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