1-178833443-A-G

Variant names:

• chr1-178833443-A-G
• rs779308103
• NM_152663.5:c.500A>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.500A>G​(p.Lys167Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000681 in 1,512,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: RALGPS2 NM_152663.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.81
• Publications: 1 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=0.23627707).

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.500A>G	p.Lys167Arg	missense	Exon 8 of 20	NP_689876.2
	RALGPS2	NM_001286247.2		c.500A>G	p.Lys167Arg	missense	Exon 8 of 19	NP_001273176.1	Q86X27-3
	RALGPS2	NM_001400042.1		c.500A>G	p.Lys167Arg	missense	Exon 8 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.500A>G	p.Lys167Arg	missense	Exon 8 of 20	ENSP00000356607.3	Q86X27-1
	RALGPS2	ENST00000853433.1		c.500A>G	p.Lys167Arg	missense	Exon 8 of 20	ENSP00000523492.1
	RALGPS2	ENST00000853430.1		c.494A>G	p.Lys165Arg	missense	Exon 8 of 20	ENSP00000523489.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000419 AC: 7 AN: 167210 AF XY: 0.0000215

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000813

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000750 AC: 102 AN: 1360234 Hom.: 0 Cov.: 30 AF XY: 0.0000622 AC XY: 42 AN XY: 674826

African (AFR) AF: 0.00 AC: 0 AN: 26746

American (AMR) AF: 0.00 AC: 0 AN: 21636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22624

East Asian (EAS) AF: 0.00 AC: 0 AN: 32618

South Asian (SAS) AF: 0.00 AC: 0 AN: 68862

European-Finnish (FIN) AF: 0.0000195 AC: 1 AN: 51360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5354

European-Non Finnish (NFE) AF: 0.0000818 AC: 88 AN: 1075180

Other (OTH) AF: 0.000233 AC: 13 AN: 55854

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74296

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67932

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000603 Hom.: 0

Bravo AF: 0.0000264

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000577 AC: 7

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	0.078
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T
Eigen	Benign	0.056
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.84	L
PhyloP100		8.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.16
Sift	Benign	0.26	T
Sift4G	Benign	0.57	T
Polyphen		0.23	B
Vest4		0.61
MutPred		0.43		Loss of ubiquitination at K167 (P = 0.0412)
MVP		0.29
MPC		0.42
ClinPred		0.18	T
GERP RS		6.0
Varity_R		0.36
gMVP		0.48
Mutation Taster		=58/42	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: rs779308103; hg19: chr1-178802578;