chr1-155948014-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001162383.2(ARHGEF2):c.2889C>A(p.Asp963Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000438 in 1,551,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

ARHGEF2
NM_001162383.2 missense, splice_region

Scores

Splicing: ADA: 0.00005092

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.753

Publications

1 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.028553724).

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.2889C>A	p.Asp963Glu	missense splice_region	Exon 22 of 22	NP_001155855.1	Q92974-1
ARHGEF2	NM_001162384.2		c.2886C>A	p.Asp962Glu	missense splice_region	Exon 22 of 22	NP_001155856.1	Q92974-2
ARHGEF2	NM_001350112.2		c.2865C>A	p.Asp955Glu	missense splice_region	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.2889C>A	p.Asp963Glu	missense splice_region	Exon 22 of 22	ENSP00000354837.4	Q92974-1
ARHGEF2	ENST00000313667.8	TSL:1	c.2886C>A	p.Asp962Glu	missense splice_region	Exon 22 of 22	ENSP00000314787.4	Q92974-2
ARHGEF2	ENST00000313695.11	TSL:1	c.2805C>A	p.Asp935Glu	missense splice_region	Exon 22 of 22	ENSP00000315325.7	Q92974-3

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152208

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:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000518

AC:

AN:

154368

AF XY:

0.0000857

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:

0.000119

Gnomad OTH exome

AF:

0.000229

GnomAD4 exome

AF:

0.0000443

AC:

AN:

1398842

Hom.:

Cov.:

AF XY:

0.0000565

AC XY:

AN XY:

689960

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31588

American (AMR)

AF:

0.0000280

AC:

AN:

35684

Ashkenazi Jewish (ASJ)

AF:

0.0000795

AC:

AN:

25170

East Asian (EAS)

AF:

0.00

AC:

AN:

35868

South Asian (SAS)

AF:

0.00

AC:

AN:

79178

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49026

Middle Eastern (MID)

AF:

0.000351

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.0000482

AC:

AN:

1078666

Other (OTH)

AF:

0.0000863

AC:

AN:

57970

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

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:

0.0000394

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41566

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000203

AC:

ClinVar

ClinVar submissions as Germline

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

Benign

0.17

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.60

CADD

Benign

5.0

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.019

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.67

M_CAP

Benign

0.0090

MetaRNN

Benign

0.029

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PhyloP100

-0.75

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.10

REVEL

Benign

0.084

Sift

Benign

0.36

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.054

MVP

0.27

MPC

0.45

ClinPred

0.038

GERP RS

-3.2

Varity_R

0.071

gMVP

0.078

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000051

dbscSNV1_RF

Benign

0.0

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over