Genetic Variant NM_020343.4:c.5232G>C (chr20-20495252-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020343.4(RALGAPA2):c.5232G>C(p.Glu1744Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,386,140 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E1744K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

RALGAPA2
NM_020343.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.26

Publications

0 publications found

Variant links:

Genes affected

RALGAPA2 (HGNC:16207): (Ral GTPase activating protein catalytic subunit alpha 2) Predicted to enable GTPase activator activity and protein heterodimerization activity. Predicted to be involved in activation of GTPase activity. Predicted to act upstream of or within Ral protein signal transduction; regulation of exocyst localization; and regulation of protein localization. Located in cytosol and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

RALGAPA2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020343.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RALGAPA2	NM_020343.4	MANE Select	c.5232G>C	p.Glu1744Asp	missense	Exon 36 of 40	NP_065076.2	Q2PPJ7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RALGAPA2	ENST00000202677.12	TSL:5 MANE Select	c.5232G>C	p.Glu1744Asp	missense	Exon 36 of 40	ENSP00000202677.6	Q2PPJ7-1
RALGAPA2	ENST00000909985.1		c.5193G>C	p.Glu1731Asp	missense	Exon 36 of 40	ENSP00000580044.1
RALGAPA2	ENST00000934890.1		c.5094G>C	p.Glu1698Asp	missense	Exon 35 of 39	ENSP00000604949.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000849

AC:

AN:

235454

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000184

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1386140

Hom.:

Cov.:

AF XY:

0.0000117

AC XY:

AN XY:

685084

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32268

American (AMR)

AF:

0.00

AC:

AN:

41518

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24280

East Asian (EAS)

AF:

0.00

AC:

AN:

38110

South Asian (SAS)

AF:

0.00

AC:

AN:

75346

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50850

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5478

European-Non Finnish (NFE)

AF:

0.0000179

AC:

AN:

1061902

Other (OTH)

AF:

0.0000177

AC:

AN:

56388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

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

0.97

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.42

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

Eigen

Benign

0.15

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.71

MetaSVM

Uncertain

-0.18

MutationAssessor

Pathogenic

3.4

PhyloP100

1.3

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.7

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.90

MutPred

0.46

Gain of helix (P = 0.1736)

MVP

0.68

MPC

0.39

ClinPred

0.99

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.75

gMVP

0.61

Mutation Taster

=84/16

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