dbSNP rs754434988: ARHGEF2:p.Glu652Lys (chr1-155952658-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001162383.2(ARHGEF2):c.1954G>A(p.Glu652Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,460,932 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

ARHGEF2
NM_001162383.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.50

Publications

2 publications found

Variant links:

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)

ARHGEF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGEF2	NM_001162383.2	MANE Select	c.1954G>A	p.Glu652Lys	missense	Exon 15 of 22	NP_001155855.1	Q92974-1
ARHGEF2	NM_001162384.2		c.1951G>A	p.Glu651Lys	missense	Exon 15 of 22	NP_001155856.1	Q92974-2
ARHGEF2	NM_001350112.2		c.1900G>A	p.Glu634Lys	missense	Exon 15 of 22	NP_001337041.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGEF2	ENST00000361247.9	TSL:1 MANE Select	c.1954G>A	p.Glu652Lys	missense	Exon 15 of 22	ENSP00000354837.4	Q92974-1
ARHGEF2	ENST00000313667.8	TSL:1	c.1951G>A	p.Glu651Lys	missense	Exon 15 of 22	ENSP00000314787.4	Q92974-2
ARHGEF2	ENST00000313695.11	TSL:1	c.1870G>A	p.Glu624Lys	missense	Exon 15 of 22	ENSP00000315325.7	Q92974-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000279

AC:

AN:

251000

AF XY:

0.0000369

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1460932

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726600

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000234

AC:

AN:

1111258

Other (OTH)

AF:

0.0000166

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.028

MetaRNN

Uncertain

0.74

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.2

PhyloP100

6.5

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.39

Sift

Benign

0.13

Sift4G

Benign

0.22

Polyphen

1.0

Vest4

0.69

MutPred

0.52

Gain of ubiquitination at E652 (P = 0.0192)

MVP

0.94

MPC

2.2

ClinPred

0.42

GERP RS

5.1

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.1

Varity_R

0.17

gMVP

0.85

Mutation Taster

=79/21

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over