Genetic Variant RALGAPA2:p.Glu1744Lys (chr20-20495254-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

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

The NM_020343.4(RALGAPA2):c.5230G>A(p.Glu1744Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000718 in 1,532,514 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 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000072 ( 0 hom. )

Consequence

RALGAPA2
NM_020343.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.85

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 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, 0.837

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RALGAPA2	NM_020343.4 link	c.5230G>A	p.Glu1744Lys	missense_variant	Exon 36 of 40	ENST00000202677.12	NP_065076.2	Q2PPJ7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RALGAPA2	ENST00000202677.12 link	c.5230G>A	p.Glu1744Lys	missense_variant	Exon 36 of 40	5	NM_020343.4	ENSP00000202677.6	Q2PPJ7-1
RALGAPA2	ENST00000430436.5 link	c.4678G>A	p.Glu1560Lys	missense_variant	Exon 30 of 33	5		ENSP00000400085.1	H7C1F9
RALGAPA2	ENST00000427175.2 link	c.460G>A	p.Glu154Lys	missense_variant	Exon 5 of 6	2		ENSP00000388695.1	H7BZA8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD3 exomes

AF:

0.0000128

AC:

AN:

235234

Hom.:

AF XY:

0.0000234

AC XY:

AN XY:

127940

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000599

Gnomad SAS exome

AF:

0.0000713

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000724

AC:

AN:

1380360

Hom.:

Cov.:

AF XY:

0.0000117

AC XY:

AN XY:

681302

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000242

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000263

Gnomad4 SAS exome

AF:

0.0000402

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000378

Gnomad4 OTH exome

AF:

0.0000178

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5230G>A (p.E1744K) alteration is located in exon 36 (coding exon 36) of the RALGAPA2 gene. This alteration results from a G to A substitution at nucleotide position 5230, causing the glutamic acid (E) at amino acid position 1744 to be replaced by a lysine (K). 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

0.97

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.62

D;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Pathogenic

0.84

MutationAssessor

Uncertain

2.7

M;.

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.6

D;.

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;T

Polyphen

1.0

D;.

Vest4

0.90

MutPred

0.58

Gain of MoRF binding (P = 0.0145);.;

MVP

0.88

MPC

0.46

ClinPred

0.97

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.83

gMVP

0.75

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over