chr1-178784515-A-G

Position:

• chr1-178784515-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_152663.5(RALGPS2):​c.155A>G​(p.Glu52Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RALGPS2 NM_152663.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.71

Genes affected

RALGPS2 (HGNC:30279): (Ral GEF with PH domain and SH3 binding motif 2) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of Ral protein signal transduction; regulation of catalytic activity; and small GTPase mediated signal transduction. Predicted to be located in cytoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

RALGPS2 (HGNC:):

ACMG classification

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, 0.756

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RALGPS2	NM_152663.5	c.155A>G	p.Glu52Gly	missense_variant	3/20	ENST00000367635.8	NP_689876.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RALGPS2	ENST00000367635.8	c.155A>G	p.Glu52Gly	missense_variant	3/20	1	NM_152663.5	ENSP00000356607.3
RALGPS2	ENST00000367634.7	c.155A>G	p.Glu52Gly	missense_variant	3/19	2		ENSP00000356606.2
RALGPS2	ENST00000324778.5	c.58-1042A>G		intron_variant		5		ENSP00000313613.5
RALGPS2	ENST00000495034.5	n.493A>G		non_coding_transcript_exon_variant	3/10	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2023

The c.155A>G (p.E52G) alteration is located in exon 3 (coding exon 2) of the RALGPS2 gene. This alteration results from a A to G substitution at nucleotide position 155, causing the glutamic acid (E) at amino acid position 52 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	0.83
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Pathogenic	3.4	M;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.012	D;D
Sift4G	Benign	0.070	T;T
Polyphen		0.76	.;P
Vest4		0.76
MutPred		0.72		Loss of stability (P = 0.032);Loss of stability (P = 0.032);
MVP		0.26
MPC		0.74
ClinPred		0.98	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.78
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-178753650;