chr1-155950335-C-A

Position:

• chr1-155950335-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 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. 13/20 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

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ARHGEF2. . Gene score misZ 3.6056 (greater than the threshold 3.09). Trascript score misZ 4.3595 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with midbrain and hindbrain malformations.
• 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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF2	NM_001162383.2	c.2851G>T	p.Gly951Cys	missense_variant	21/22	ENST00000361247.9	NP_001155855.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF2	ENST00000361247.9	c.2851G>T	p.Gly951Cys	missense_variant	21/22	1	NM_001162383.2	ENSP00000354837	P4

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

GnomAD3 exomes AF: 0.00214 AC: 537 AN: 250974 Hom.: 3 AF XY: 0.00161 AC XY: 219 AN XY: 135706

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 SAS 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

Gnomad4 AFR exome AF: 0.0317

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00108

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

Gnomad4 AFR AF: 0.0280

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.000972 Hom.: 4

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

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;T;.
Eigen	Benign	0.062
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.87	D;D;D;D
MetaRNN	Benign	0.0031	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.5	N;N;.;N
REVEL	Benign	0.097
Sift	Benign	0.092	T;T;.;T
Sift4G	Benign	0.10	T;T;T;T
Polyphen		0.70, 0.80	.;P;.;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

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: rs56794580; hg19: chr1-155920126;