5-81225762-C-T

Variant names:

• chr5-81225762-C-T
• rs1387208549
• NM_006909.3:c.3706C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006909.3(RASGRF2):​c.3706C>T​(p.Pro1236Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,459,492 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RASGRF2 NM_006909.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.69

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]

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

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35413802).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGRF2	NM_006909.3	c.3706C>T	p.Pro1236Ser	missense_variant	Exon 27 of 27	ENST00000265080.9	NP_008840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASGRF2	ENST00000265080.9	c.3706C>T	p.Pro1236Ser	missense_variant	Exon 27 of 27	1	NM_006909.3	ENSP00000265080.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000806 AC: 2 AN: 248054 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134100

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 SAS exome AF: 0.0000676

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459492 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725980

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3706C>T (p.P1236S) alteration is located in exon 1 (coding exon 1) of the RASGRF2 gene. This alteration results from a C to T substitution at nucleotide position 3706, causing the proline (P) at amino acid position 1236 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	Uncertain	0.50
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.057	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	1.5	L
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.023	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.31
MutPred		0.41		Gain of phosphorylation at P1236 (P = 0.0069);
MVP		0.45
MPC		1.2
ClinPred		0.81	D
GERP RS		5.2
Varity_R		0.23
gMVP		0.48

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

LitVar

Other links and lift over

dbSNP: rs1387208549; hg19: chr5-80521581;