NM_004489.5:c.877G>C

Variant names:

• chr17-7313052-C-G
• rs2072883633
• NM_004489.5:c.877G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004489.5(GPS2):​c.877G>C​(p.Val293Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 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. V293E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GPS2 NM_004489.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.36
• Publications: 0 publications found

Genes affected

GPS2 (HGNC:4550): (G protein pathway suppressor 2) This gene encodes a protein involved in G protein-mitogen-activated protein kinase (MAPK) signaling cascades. When overexpressed in mammalian cells, this gene could potently suppress a RAS- and MAPK-mediated signal and interfere with JNK activity, suggesting that the function of this gene may be signal repression. The encoded protein is an integral subunit of the NCOR1-HDAC3 (nuclear receptor corepressor 1-histone deacetylase 3) complex, and it was shown that the complex inhibits JNK activation through this subunit and thus could potentially provide an alternative mechanism for hormone-mediated antagonism of AP1 (activator protein 1) function. [provided by RefSeq, Jul 2008]

ENSG00000261915 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29339015).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004489.5. 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
	GPS2	NM_004489.5	MANE Select	c.877G>C	p.Val293Leu	missense	Exon 10 of 11	NP_004480.1	Q13227-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPS2	ENST00000380728.7	TSL:1 MANE Select	c.877G>C	p.Val293Leu	missense	Exon 10 of 11	ENSP00000370104.2	Q13227-1
	GPS2	ENST00000389167.9	TSL:1	c.877G>C	p.Val293Leu	missense	Exon 9 of 10	ENSP00000379841.4	Q13227-1
	GPS2	ENST00000571569.5	TSL:1	n.1382G>C		non_coding_transcript_exon	Exon 9 of 10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.23
BayesDel_addAF	Benign	0.0013	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.4
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.57
MutPred		0.15		Loss of sheet (P = 0.0104)
MVP		0.52
ClinPred		0.94	D
GERP RS		3.6
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.30
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2072883633; hg19: chr17-7216371;