rs56794580

Variant names:

• chr1-155950335-C-A
• rs56794580
• NM_001162383.2:c.2851G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-155950335-C-A
• chr1-155950335-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001162383.2(ARHGEF2):​c.2851G>T​(p.Gly951Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,613,694 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (18 hom.)
• Consequence: ARHGEF2 NM_001162383.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.08
• Publications: 4 publications found

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]

ARHGEF2 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with midbrain and hindbrain malformations

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030596256).
• BP6: Variant 1-155950335-C-A is Benign according to our data. Variant chr1-155950335-C-A is described in ClinVar as Benign. ClinVar VariationId is 773284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00801 (1220/152340) while in subpopulation AFR AF = 0.028 (1165/41586). AF 95% confidence interval is 0.0267. There are 15 homozygotes in GnomAd4. There are 581 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001162383.2. 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
	ARHGEF2	NM_001162383.2	MANE Select	c.2851G>T	p.Gly951Cys	missense	Exon 21 of 22	NP_001155855.1	Q92974-1
	ARHGEF2	NM_001162384.2		c.2848G>T	p.Gly950Cys	missense	Exon 21 of 22	NP_001155856.1	Q92974-2
	ARHGEF2	NM_001350112.2		c.2797G>T	p.Gly933Cys	missense	Exon 21 of 22	NP_001337041.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF2	ENST00000361247.9	TSL:1 MANE Select	c.2851G>T	p.Gly951Cys	missense	Exon 21 of 22	ENSP00000354837.4	Q92974-1
	ARHGEF2	ENST00000313667.8	TSL:1	c.2848G>T	p.Gly950Cys	missense	Exon 21 of 22	ENSP00000314787.4	Q92974-2
	ARHGEF2	ENST00000313695.11	TSL:1	c.2767G>T	p.Gly923Cys	missense	Exon 21 of 22	ENSP00000315325.7	Q92974-3

Frequencies

GnomAD3 genomes AF: 0.00801 AC: 1220 AN: 152222 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

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: 0.000103

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00214 AC: 537 AN: 250974 AF XY: 0.00161

Gnomad AFR exome AF: 0.0297

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000818 AC: 1195 AN: 1461354 Hom.: 18 Cov.: 31 AF XY: 0.000704 AC XY: 512 AN XY: 726978

African (AFR) AF: 0.0317 AC: 1062 AN: 33476

American (AMR) AF: 0.00125 AC: 56 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53024

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5682

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111986

Other (OTH) AF: 0.00108 AC: 65 AN: 60376

GnomAD4 genome AF: 0.00801 AC: 1220 AN: 152340 Hom.: 15 Cov.: 32 AF XY: 0.00780 AC XY: 581 AN XY: 74502

African (AFR) AF: 0.0280 AC: 1165 AN: 41586

American (AMR) AF: 0.00222 AC: 34 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68028

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00261 Hom.: 12

Bravo AF: 0.00908

ESP6500AA AF: 0.0261 AC: 115

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00259 AC: 314

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.043	T
Eigen	Benign	0.062
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.097
Sift	Benign	0.092	T
Sift4G	Benign	0.10	T
Polyphen		0.70	P
Vest4		0.37
MVP		0.59
MPC		1.1
ClinPred		0.012	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.15
gMVP		0.27
Mutation Taster		=100/0	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: rs56794580; hg19: chr1-155920126;