1-178776771-C-G

Variant names:

• chr1-178776771-C-G
• rs1364789654
• NM_152663.5:c.7C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152663.5(RALGPS2):​c.7C>G​(p.Leu3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,611,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RALGPS2 NM_152663.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.82
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11073226).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152663.5. 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
	RALGPS2	NM_152663.5	MANE Select	c.7C>G	p.Leu3Val	missense	Exon 2 of 20	NP_689876.2
	RALGPS2	NM_001286247.2		c.7C>G	p.Leu3Val	missense	Exon 2 of 19	NP_001273176.1	Q86X27-3
	RALGPS2	NM_001400042.1		c.7C>G	p.Leu3Val	missense	Exon 2 of 19	NP_001386971.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RALGPS2	ENST00000367635.8	TSL:1 MANE Select	c.7C>G	p.Leu3Val	missense	Exon 2 of 20	ENSP00000356607.3	Q86X27-1
	RALGPS2	ENST00000853433.1		c.7C>G	p.Leu3Val	missense	Exon 2 of 20	ENSP00000523492.1
	RALGPS2	ENST00000853430.1		c.7C>G	p.Leu3Val	missense	Exon 2 of 20	ENSP00000523489.1

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151652 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.000480

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460322 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726482

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.0000672 AC: 3 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 AN: 86160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111024

Other (OTH) AF: 0.00 AC: 0 AN: 60280

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151652 Hom.: 0 Cov.: 30 AF XY: 0.0000405 AC XY: 3 AN XY: 74012

African (AFR) AF: 0.0000242 AC: 1 AN: 41262

American (AMR) AF: 0.000197 AC: 3 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.000480 AC: 1 AN: 2084

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.0098
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.8
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.059
Sift	Benign	0.11	T
Sift4G	Benign	0.51	T
Polyphen		0.0030	B
Vest4		0.30
MutPred		0.41		Gain of catalytic residue at L3 (P = 0.0718)
MVP		0.17
MPC		0.46
ClinPred		0.41	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.37
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

dbSNP: rs1364789654; hg19: chr1-178745906;