Genetic Variant RASAL2:p.Asp26Tyr (chr1-178094568-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_170692.4(RASAL2):c.76G>T(p.Asp26Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RASAL2
NM_170692.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.83

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20342427).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASAL2	NM_170692.4 link	c.76G>T	p.Asp26Tyr	missense_variant	Exon 1 of 18	ENST00000367649.8	NP_733793.2	Q9UJF2-2
RASAL2	XM_011510166.3 link	c.76G>T	p.Asp26Tyr	missense_variant	Exon 1 of 19		XP_011508468.1
RASAL2	XM_011510167.3 link	c.76G>T	p.Asp26Tyr	missense_variant	Exon 1 of 18		XP_011508469.1
RASAL2	XM_047434837.1 link	c.76G>T	p.Asp26Tyr	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.76G>T	p.Asp26Tyr	missense_variant	Exon 1 of 18	1	NM_170692.4	ENSP00000356621.3		Q9UJF2-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1448398

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719522

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 24, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.76G>T (p.D26Y) alteration is located in exon 1 (coding exon 1) of the RASAL2 gene. This alteration results from a G to T substitution at nucleotide position 76, causing the aspartic acid (D) at amino acid position 26 to be replaced by a tyrosine (Y). 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

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

DANN

Uncertain

0.99

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.82

M_CAP

Benign

0.0086

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.98

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.4

REVEL

Benign

0.068

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.014

Vest4

0.30

MutPred

0.26

Loss of solvent accessibility (P = 0.0152);

MVP

0.27

MPC

0.40

ClinPred

0.99

GERP RS

4.7

gMVP

0.35

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over