Genetic Variant RASAL2:p.Pro28Gln (chr1-178094575-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_170692.4(RASAL2):c.83C>A(p.Pro28Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,604,602 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000096 ( 1 hom. )

Consequence

RASAL2
NM_170692.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.06

Variant links:

Genes affected

RASAL2 (HGNC:9874): (RAS protein activator like 2) This gene encodes a protein that contains the GAP-related domain (GRD), a characteristic domain of GTPase-activating proteins (GAPs). GAPs function as activators of Ras superfamily of small GTPases. The protein encoded by this gene is able to complement the defective RasGAP function in a yeast system. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

RASAL2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.006712407).

BP6

Variant 1-178094575-C-A is Benign according to our data. Variant chr1-178094575-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 721721.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASAL2	NM_170692.4 link	c.83C>A	p.Pro28Gln	missense_variant	Exon 1 of 18	ENST00000367649.8	NP_733793.2	Q9UJF2-2
RASAL2	XM_011510166.3 link	c.83C>A	p.Pro28Gln	missense_variant	Exon 1 of 19		XP_011508468.1
RASAL2	XM_011510167.3 link	c.83C>A	p.Pro28Gln	missense_variant	Exon 1 of 18		XP_011508469.1
RASAL2	XM_047434837.1 link	c.83C>A	p.Pro28Gln	missense_variant	Exon 1 of 19		XP_047290793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASAL2	ENST00000367649.8 link	c.83C>A	p.Pro28Gln	missense_variant	Exon 1 of 18	1	NM_170692.4	ENSP00000356621.3		Q9UJF2-2

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00289

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000227

AC:

AN:

229504

Hom.:

AF XY:

0.000192

AC XY:

AN XY:

124754

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000304

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00294

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000985

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000957

AC:

139

AN:

1452248

Hom.:

Cov.:

AF XY:

0.0000928

AC XY:

AN XY:

721734

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.0000230

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00212

Gnomad4 SAS exome

AF:

0.0000236

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000542

Gnomad4 OTH exome

AF:

0.000767

GnomAD4 genome

AF:

0.000164

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000522

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00289

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.0000225

Hom.:

Bravo

AF:

0.000242

ExAC

AF:

0.000280

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Uncertain

DANN

Uncertain

0.99

Eigen

Benign

0.068

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.76

M_CAP

Benign

0.012

MetaRNN

Benign

0.0067

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.73

REVEL

Benign

0.045

Sift

Uncertain

0.017

Sift4G

Pathogenic

0.0

Vest4

0.34

MutPred

0.20

Loss of glycosylation at S25 (P = 0.0732);

MVP

0.26

MPC

0.64

ClinPred

0.089

GERP RS

4.7

gMVP

0.32

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