NM_001162383.2:c.1949G>T

Variant names:

• chr1-155952663-C-A
• rs1296321151
• NM_001162383.2:c.1949G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001162383.2(ARHGEF2):​c.1949G>T​(p.Arg650Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,444 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R650H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ARHGEF2 NM_001162383.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.84

Genes affected

ARHGEF2 (HGNC:682): (Rho/Rac guanine nucleotide exchange factor 2) Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The encoded protein may form complex with G proteins and stimulate rho-dependent signals. Alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF2	NM_001162383.2	c.1949G>T	p.Arg650Leu	missense_variant	Exon 15 of 22	ENST00000361247.9	NP_001155855.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF2	ENST00000361247.9	c.1949G>T	p.Arg650Leu	missense_variant	Exon 15 of 22	1	NM_001162383.2	ENSP00000354837.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251128 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135764

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461444 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726970

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	0.0094	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T;T;T;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.62	D;D;D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.8	.;L;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.8	D;D;.;D;D
REVEL	Benign	0.23
Sift	Benign	0.054	T;T;.;T;D
Sift4G	Uncertain	0.020	D;D;D;D;D
Polyphen		0.99, 0.97	.;D;.;.;D
Vest4		0.80
MutPred		0.35		.;Loss of methylation at R650 (P = 0.0851);.;.;.;
MVP		0.75
MPC		2.2
ClinPred		0.96	D
GERP RS		4.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.30
gMVP		0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs1296321151; hg19: chr1-155922454;