1-178420572-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_170692.4(RASAL2):​c.626A>G​(p.Asp209Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

RASAL2
NM_170692.4 missense

Scores

9
9
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.22
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.819

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RASAL2NM_170692.4 linkc.626A>G p.Asp209Gly missense_variant Exon 5 of 18 ENST00000367649.8 NP_733793.2 Q9UJF2-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RASAL2ENST00000367649.8 linkc.626A>G p.Asp209Gly missense_variant Exon 5 of 18 1 NM_170692.4 ENSP00000356621.3 Q9UJF2-2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250680
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135466
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1460948
Hom.:
0
Cov.:
30
AF XY:
0.00000413
AC XY:
3
AN XY:
726768
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:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152202
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000508
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 25, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.626A>G (p.D209G) alteration is located in exon 5 (coding exon 5) of the RASAL2 gene. This alteration results from a A to G substitution at nucleotide position 626, causing the aspartic acid (D) at amino acid position 209 to be replaced by a glycine (G). 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
0.68
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.46
.;T
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.82
D;D
MetaSVM
Uncertain
0.26
D
MutationAssessor
Uncertain
2.7
.;M
PrimateAI
Uncertain
0.78
T
PROVEAN
Pathogenic
-4.5
D;D
REVEL
Uncertain
0.57
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.016
D;D
Polyphen
0.96
.;D
Vest4
0.85
MutPred
0.12
.;Loss of stability (P = 0.0578);
MVP
0.85
MPC
0.97
ClinPred
0.99
D
GERP RS
5.5
Varity_R
0.68
gMVP
0.50

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.

Other links and lift over

dbSNP: rs1468783422; hg19: chr1-178389707; API