Genetic Variant RABL2A:p.Gly33Arg (chr2-113628703-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_001306158.2(RABL2A):c.97G>C(p.Gly33Arg) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 18)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RABL2A
NM_001306158.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.75

Variant links:

Genes affected

RABL2A (HGNC:9799): (RAB, member of RAS oncogene family like 2A) This gene is a member of the RAB gene family which belongs to the RAS GTPase superfamily. The proteins in the family of RAS-related signaling molecules are small GTP-binding proteins that play important roles in the regulation of exocytotic and endocytotic pathways. This gene maps to the site of an ancestral telomere fusion event and may be a subtelomeric gene. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

RABL2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RABL2A	NM_001306158.2 link	c.97G>C	p.Gly33Arg	missense_variant	Exon 2 of 9	ENST00000683472.1	NP_001293087.1	Q6IC14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RABL2A	ENST00000683472.1 link	c.97G>C	p.Gly33Arg	missense_variant	Exon 2 of 9		NM_001306158.2	ENSP00000507832.1		Q9UBK7-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

139676

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0000279

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000153

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000433

AC:

AN:

1385596

Hom.:

Cov.:

AF XY:

0.00000726

AC XY:

AN XY:

688254

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000569

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000143

AC:

AN:

139676

Hom.:

Cov.:

AF XY:

0.0000148

AC XY:

AN XY:

67452

show subpopulations

Gnomad4 AFR

AF:

0.0000279

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000153

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.97G>C (p.G33R) alteration is located in exon 2 (coding exon 1) of the RABL2A gene. This alteration results from a G to C substitution at nucleotide position 97, causing the glycine (G) at amino acid position 33 to be replaced by an arginine (R). 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

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;.;.;.;D;.;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

.;.;D;D;D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

4.5

H;.;.;H;H;H;.

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-7.4

D;D;D;D;D;D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0010

D;D;D;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D;D;D

Polyphen

1.0

D;D;.;.;D;.;D

Vest4

0.78

MutPred

0.93

Gain of MoRF binding (P = 0.0239);Gain of MoRF binding (P = 0.0239);Gain of MoRF binding (P = 0.0239);Gain of MoRF binding (P = 0.0239);Gain of MoRF binding (P = 0.0239);Gain of MoRF binding (P = 0.0239);Gain of MoRF binding (P = 0.0239);

MVP

0.99

MPC

3.3

ClinPred

1.0

GERP RS

2.1

Varity_R

0.68

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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