chr1-178776804-G-T

Position:

• chr1-178776804-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152663.5(RALGPS2):​c.40G>T​(p.Ala14Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. A14G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: RALGPS2 NM_152663.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07215682).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RALGPS2	NM_152663.5	c.40G>T	p.Ala14Ser	missense_variant	2/20	ENST00000367635.8	NP_689876.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RALGPS2	ENST00000367635.8	c.40G>T	p.Ala14Ser	missense_variant	2/20	1	NM_152663.5	ENSP00000356607.3
RALGPS2	ENST00000367634.7	c.40G>T	p.Ala14Ser	missense_variant	2/19	2		ENSP00000356606.2
RALGPS2	ENST00000324778.5	c.40G>T	p.Ala14Ser	missense_variant	2/10	5		ENSP00000313613.5
RALGPS2	ENST00000495034.5	n.378G>T		non_coding_transcript_exon_variant	2/10	2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

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

Aug 18, 2023

The c.40G>T (p.A14S) alteration is located in exon 2 (coding exon 1) of the RALGPS2 gene. This alteration results from a G to T substitution at nucleotide position 40, causing the alanine (A) at amino acid position 14 to be replaced by a serine (S). 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	Benign	0.079
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.0091	.;T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.86	D;D;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.072	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.050	N;N;N
REVEL	Benign	0.038
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.72	T;T;T
Polyphen		0.0020	.;B;.
Vest4		0.36
MutPred		0.24		Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);
MVP		0.17
MPC		0.42
ClinPred		0.52	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.061
gMVP		0.47

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: chr1-178745939;