Genetic Variant NM_170692.4:c.8T>G (chr1-178094500-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_170692.4(RASAL2):c.8T>G(p.Leu3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000045 in 1,555,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

RASAL2
NM_170692.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.05

Publications

0 publications found

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:

RASAL2-AS1 (HGNC:44170): (RASAL2 antisense RNA 1)

RASAL2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11808795).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170692.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASAL2	NM_170692.4	MANE Select	c.8T>G	p.Leu3Arg	missense	Exon 1 of 18	NP_733793.2	Q9UJF2-2
RASAL2	NM_001437625.1		c.8T>G	p.Leu3Arg	missense	Exon 1 of 19	NP_001424554.1
RASAL2	NM_001437626.1		c.8T>G	p.Leu3Arg	missense	Exon 1 of 18	NP_001424555.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASAL2	ENST00000367649.8	TSL:1 MANE Select	c.8T>G	p.Leu3Arg	missense	Exon 1 of 18	ENSP00000356621.3	Q9UJF2-2
RASAL2	ENST00000902905.1		c.8T>G	p.Leu3Arg	missense	Exon 1 of 18	ENSP00000572964.1
RASAL2-AS1	ENST00000767999.1		n.-56A>C		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000131

AC:

AN:

152328

AF XY:

0.0000241

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000396

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000175

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000428

AC:

AN:

1402884

Hom.:

Cov.:

AF XY:

0.00000433

AC XY:

AN XY:

692902

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31790

American (AMR)

AF:

0.0000275

AC:

AN:

36422

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25206

East Asian (EAS)

AF:

0.00

AC:

AN:

36080

South Asian (SAS)

AF:

0.00

AC:

AN:

79856

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4692

European-Non Finnish (NFE)

AF:

0.00000462

AC:

AN:

1083152

Other (OTH)

AF:

0.00

AC:

AN:

58120

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.083

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.58

M_CAP

Benign

0.033

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.1

PhyloP100

1.0

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.10

REVEL

Benign

0.041

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.31

MutPred

0.18

Loss of sheet (P = 0.0228)

MVP

0.19

MPC

0.94

ClinPred

0.63

GERP RS

4.7

PromoterAI

-0.15

Neutral

(source)

gMVP

0.47

Mutation Taster

=92/8

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over