rs1010033

Variant names:

• chr1-155948089-T-A
• rs1010033
• NM_001162383.2:c.2888-74A>T

Your query was ambiguous. Multiple possible variants found:

• chr1-155948089-T-A
• chr1-155948089-T-C
• chr1-155948089-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001162383.2(ARHGEF2):​c.2888-74A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.897 in 1,195,820 control chromosomes in the GnomAD database, including 486,543 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (51648 hom., cov: 31)
  • Exomes 𝑓: 0.91 (434895 hom.)
• Consequence: ARHGEF2 NM_001162383.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.372
• Publications: 6 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-155948089-T-A is Benign according to our data. Variant chr1-155948089-T-A is described in ClinVar as Benign. ClinVar VariationId is 1192410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.918 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF2	NM_001162383.2	MANE Select	c.2888-74A>T		intron	N/A	NP_001155855.1	Q92974-1
	ARHGEF2	NM_001162384.2		c.2885-74A>T		intron	N/A	NP_001155856.1	Q92974-2
	ARHGEF2	NM_001350112.2		c.2864-74A>T		intron	N/A	NP_001337041.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF2	ENST00000361247.9	TSL:1 MANE Select	c.2888-74A>T		intron	N/A	ENSP00000354837.4	Q92974-1
	ARHGEF2	ENST00000313667.8	TSL:1	c.2885-74A>T		intron	N/A	ENSP00000314787.4	Q92974-2
	ARHGEF2	ENST00000313695.11	TSL:1	c.2804-74A>T		intron	N/A	ENSP00000315325.7	Q92974-3

Frequencies

GnomAD3 genomes AF: 0.805 AC: 122296 AN: 151940 Hom.: 51637 Cov.: 31

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.903

Gnomad ASJ AF: 0.876

Gnomad EAS AF: 0.940

Gnomad SAS AF: 0.864

Gnomad FIN AF: 0.892

Gnomad MID AF: 0.813

Gnomad NFE AF: 0.924

Gnomad OTH AF: 0.839

GnomAD4 exome AF: 0.910 AC: 949745 AN: 1043762 Hom.: 434895 AF XY: 0.909 AC XY: 473671 AN XY: 521186

African (AFR) AF: 0.505 AC: 12122 AN: 24022

American (AMR) AF: 0.936 AC: 27266 AN: 29142

Ashkenazi Jewish (ASJ) AF: 0.879 AC: 18979 AN: 21594

East Asian (EAS) AF: 0.946 AC: 30393 AN: 32112

South Asian (SAS) AF: 0.855 AC: 55217 AN: 64612

European-Finnish (FIN) AF: 0.896 AC: 42693 AN: 47636

Middle Eastern (MID) AF: 0.830 AC: 4081 AN: 4918

European-Non Finnish (NFE) AF: 0.928 AC: 718802 AN: 774426

Other (OTH) AF: 0.887 AC: 40192 AN: 45300

GnomAD4 genome AF: 0.804 AC: 122321 AN: 152058 Hom.: 51648 Cov.: 31 AF XY: 0.806 AC XY: 59932 AN XY: 74336

African (AFR) AF: 0.517 AC: 21419 AN: 41390

American (AMR) AF: 0.904 AC: 13817 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.876 AC: 3038 AN: 3470

East Asian (EAS) AF: 0.940 AC: 4854 AN: 5166

South Asian (SAS) AF: 0.865 AC: 4165 AN: 4816

European-Finnish (FIN) AF: 0.892 AC: 9457 AN: 10602

Middle Eastern (MID) AF: 0.813 AC: 239 AN: 294

European-Non Finnish (NFE) AF: 0.924 AC: 62855 AN: 68014

Other (OTH) AF: 0.840 AC: 1767 AN: 2104

Alfa AF: 0.859 Hom.: 6799

Bravo AF: 0.794

Asia WGS AF: 0.872 AC: 3033 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Neurodevelopmental disorder with midbrain and hindbrain malformations (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.8
DANN	Benign	0.69
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1010033; hg19: chr1-155917880;