1-178821651-G-T

Position:

• chr1-178821651-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_152663.5(RALGPS2):​c.427G>T​(p.Val143Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RALGPS2 NM_152663.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.48

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RALGPS2	NM_152663.5	c.427G>T	p.Val143Leu	missense_variant	7/20	ENST00000367635.8	NP_689876.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RALGPS2	ENST00000367635.8	c.427G>T	p.Val143Leu	missense_variant	7/20	1	NM_152663.5	ENSP00000356607.3
RALGPS2	ENST00000367634.7	c.427G>T	p.Val143Leu	missense_variant	7/19	2		ENSP00000356606.2
RALGPS2	ENST00000324778.5	c.322G>T	p.Val108Leu	missense_variant	6/10	5		ENSP00000313613.5
RALGPS2	ENST00000495034.5	n.765G>T		non_coding_transcript_exon_variant	7/10	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Nov 19, 2024

The c.427G>T (p.V143L) alteration is located in exon 7 (coding exon 6) of the RALGPS2 gene. This alteration results from a G to T substitution at nucleotide position 427, causing the valine (V) at amino acid position 143 to be replaced by a leucine (L). 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	0.69
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.095	.;T;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.2	M;M;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.013	D;D;D
Polyphen		0.97	.;D;.
Vest4		0.63
MutPred		0.84		Loss of catalytic residue at V143 (P = 0.0595);Loss of catalytic residue at V143 (P = 0.0595);.;
MVP		0.42
MPC		1.2
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.69
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr1-178790786; COSMIC: COSV61336038;