Genetic Variant NM_170692.4:c.185G>T (chr1-178094677-G-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_170692.4(RASAL2):c.185G>T(p.Ser62Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000421 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S62T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

RASAL2
NM_170692.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.62

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.036107987).

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.185G>T	p.Ser62Ile	missense	Exon 1 of 18	NP_733793.2	Q9UJF2-2
RASAL2	NM_001437625.1		c.185G>T	p.Ser62Ile	missense	Exon 1 of 19	NP_001424554.1
RASAL2	NM_001437626.1		c.185G>T	p.Ser62Ile	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.185G>T	p.Ser62Ile	missense	Exon 1 of 18	ENSP00000356621.3	Q9UJF2-2
RASAL2	ENST00000902905.1		c.185G>T	p.Ser62Ile	missense	Exon 1 of 18	ENSP00000572964.1
RASAL2-AS1	ENST00000767999.1		n.-233C>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152276

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000916

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000480

AC:

AN:

249874

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.000744

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461722

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.000836

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53276

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112006

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.000249

AC:

AN:

152394

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74530

show subpopulations

African (AFR)

AF:

0.000914

AC:

AN:

41598

American (AMR)

AF:

0.00

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000196

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

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

Pathogenic

0.65

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.52

CADD

Uncertain

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.84

M_CAP

Benign

0.0034

MetaRNN

Benign

0.036

MetaSVM

Benign

-1.0

PhyloP100

3.6

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.2

REVEL

Benign

0.067

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.027

Vest4

0.26

MVP

0.21

MPC

0.27

ClinPred

0.12

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.60

Mutation Taster

=89/11

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over