chr1-155952148-C-A

Position:

• chr1-155952148-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_001162383.2(ARHGEF2):​c.2072G>T​(p.Ser691Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGEF2 NM_001162383.2 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.106

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 3 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity ARHG2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• 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=0.17804623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF2	NM_001162383.2	c.2072G>T	p.Ser691Ile	missense_variant	16/22	ENST00000361247.9	NP_001155855.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF2	ENST00000361247.9	c.2072G>T	p.Ser691Ile	missense_variant	16/22	1	NM_001162383.2	ENSP00000354837	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Myoepithelial tumor Uncertain:1

Uncertain significance, no assertion criteria provided

research

Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine

Nov 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.071	.;T;T;T;.
Eigen	Benign	-0.047
Eigen_PC	Benign	-0.078
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.83	T;T;T;D;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.5	.;L;.;.;.
MutationTaster	Benign	0.52	D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	N;N;.;.;N
REVEL	Benign	0.054
Sift	Uncertain	0.017	D;D;.;.;D
Sift4G	Benign	0.062	T;T;T;D;T
Polyphen		0.68, 0.65	.;P;.;.;P
Vest4		0.19
MutPred		0.32		.;Loss of glycosylation at S691 (P = 0.0025);.;.;.;
MVP		0.69
MPC		0.74
ClinPred		0.46	T
GERP RS		4.5
Varity_R		0.085
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-155921939;