Genetic Variant NM_001162383.2:c.1546-79C>T (chr1-155957961-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001162383.2(ARHGEF2):c.1546-79C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,432,420 control chromosomes in the GnomAD database, including 48,704 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.26 ( 6104 hom., cov: 33)

Exomes 𝑓: 0.23 ( 42600 hom. )

Consequence

ARHGEF2
NM_001162383.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.587

Publications

19 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF2	NM_001162383.2 link	c.1546-79C>T		intron_variant	Intron 12 of 21	ENST00000361247.9	NP_001155855.1	Q92974-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF2	ENST00000361247.9 link	c.1546-79C>T		intron_variant	Intron 12 of 21	1	NM_001162383.2	ENSP00000354837.4		Q92974-1

Frequencies

GnomAD3 genomes

AF:

0.260

AC:

39509

AN:

152044

Hom.:

6092

Cov.:

show subpopulations

Gnomad AFR

AF:

0.289

Gnomad AMI

AF:

0.181

Gnomad AMR

AF:

0.296

Gnomad ASJ

AF:

0.199

Gnomad EAS

AF:

0.775

Gnomad SAS

AF:

0.301

Gnomad FIN

AF:

0.194

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.207

Gnomad OTH

AF:

0.263

GnomAD4 exome

AF:

0.234

AC:

299159

AN:

1280258

Hom.:

42600

AF XY:

0.234

AC XY:

147807

AN XY:

633004

show subpopulations

African (AFR)

AF:

0.292

AC:

8643

AN:

29566

American (AMR)

AF:

0.395

AC:

12119

AN:

30714

Ashkenazi Jewish (ASJ)

AF:

0.200

AC:

4208

AN:

21006

East Asian (EAS)

AF:

0.787

AC:

29204

AN:

37112

South Asian (SAS)

AF:

0.285

AC:

19829

AN:

69684

European-Finnish (FIN)

AF:

0.193

AC:

8910

AN:

46062

Middle Eastern (MID)

AF:

0.185

AC:

934

AN:

5048

European-Non Finnish (NFE)

AF:

0.204

AC:

201616

AN:

987106

Other (OTH)

AF:

0.254

AC:

13696

AN:

53960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

10513

21026

31539

42052

52565

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7388

14776

22164

29552

36940

<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:

0.260

AC:

39543

AN:

152162

Hom.:

6104

Cov.:

AF XY:

0.263

AC XY:

19594

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.288

AC:

11961

AN:

41474

American (AMR)

AF:

0.298

AC:

4556

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.199

AC:

690

AN:

3468

East Asian (EAS)

AF:

0.775

AC:

4006

AN:

5168

South Asian (SAS)

AF:

0.301

AC:

1452

AN:

4826

European-Finnish (FIN)

AF:

0.194

AC:

2060

AN:

10606

Middle Eastern (MID)

AF:

0.207

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.207

AC:

14045

AN:

68012

Other (OTH)

AF:

0.259

AC:

547

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1409

2817

4226

5634

7043

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

404

808

1212

1616

2020

<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:

0.233

Hom.:

12526

Bravo

AF:

0.276

Asia WGS

AF:

0.512

AC:

1779

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

4.1

(source)

DANN

Benign

0.23

PhyloP100

0.59

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over