chr5-81208394-G-C

Variant names:

• chr5-81208394-G-C
• rs556120453
• NM_006909.3:c.3112G>C

Variant summary

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

The NM_006909.3(RASGRF2):​c.3112G>C​(p.Glu1038Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1038K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RASGRF2 NM_006909.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.05
• Publications: 3 publications found

Genes affected

RASGRF2 (HGNC:9876): (Ras protein specific guanine nucleotide releasing factor 2) RAS GTPases cycle between an inactive GDP-bound state and an active GTP-bound state. This gene encodes a calcium-regulated nucleotide exchange factor activating both RAS and RAS-related protein, RAC1, through the exchange of bound GDP for GTP, thereby, coordinating the signaling of distinct mitogen-activated protein kinase pathways. [provided by RefSeq, Oct 2011]

LOC124901017 (HGNC:):

CKMT2-AS1 (HGNC:48997): (CKMT2 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006909.3. 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
	RASGRF2	NM_006909.3	MANE Select	c.3112G>C	p.Glu1038Gln	missense	Exon 22 of 27	NP_008840.1	O14827

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASGRF2	ENST00000265080.9	TSL:1 MANE Select	c.3112G>C	p.Glu1038Gln	missense	Exon 22 of 27	ENSP00000265080.4	O14827
	RASGRF2	ENST00000503795.1	TSL:1	n.3112G>C		non_coding_transcript_exon	Exon 22 of 28	ENSP00000421771.1	D6RAS9
	RASGRF2	ENST00000933988.1		c.3067G>C	p.Glu1023Gln	missense	Exon 22 of 27	ENSP00000604047.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.9	L
PhyloP100		8.1
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.19
Sift	Benign	0.081	T
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.61
MutPred		0.38		Loss of ubiquitination at K1036 (P = 0.0352)
MVP		0.29
MPC		0.93
ClinPred		0.95	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.53
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs556120453; hg19: chr5-80504213;