Genetic Variant ARHGEF2:p.Gly979Arg (chr1-155947968-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001162383.2(ARHGEF2):c.2935G>A(p.Gly979Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000645 in 1,550,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. G979W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000057 ( 0 hom. )

Consequence

ARHGEF2
NM_001162383.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.36

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2789542).

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.2935G>A	p.Gly979Arg	missense	Exon 22 of 22	NP_001155855.1	Q92974-1
ARHGEF2	NM_001162384.2		c.2932G>A	p.Gly978Arg	missense	Exon 22 of 22	NP_001155856.1	Q92974-2
ARHGEF2	NM_001350112.2		c.2911G>A	p.Gly971Arg	missense	Exon 22 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.2935G>A	p.Gly979Arg	missense	Exon 22 of 22	ENSP00000354837.4	Q92974-1
ARHGEF2	ENST00000313667.8	TSL:1	c.2932G>A	p.Gly978Arg	missense	Exon 22 of 22	ENSP00000314787.4	Q92974-2
ARHGEF2	ENST00000313695.11	TSL:1	c.2851G>A	p.Gly951Arg	missense	Exon 22 of 22	ENSP00000315325.7	Q92974-3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000130

AC:

AN:

153600

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000572

AC:

AN:

1398718

Hom.:

Cov.:

AF XY:

0.00000725

AC XY:

AN XY:

689872

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31588

American (AMR)

AF:

0.0000280

AC:

AN:

35680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25172

East Asian (EAS)

AF:

0.00

AC:

AN:

35874

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79186

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48850

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00000556

AC:

AN:

1078708

Other (OTH)

AF:

0.00

AC:

AN:

57970

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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

AF:

0.0000131

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000232

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.019

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.38

MutationAssessor

Benign

0.55

PhyloP100

4.4

PrimateAI

Uncertain

0.60

PROVEAN

Benign

0.050

REVEL

Benign

0.25

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.30

MVP

0.75

MPC

1.5

ClinPred

0.72

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.36

Mutation Taster

=89/11

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

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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