rs77345976

Variant names:

• chr1-155951747-C-A
• rs77345976
• NM_001162383.2:c.2202G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-155951747-C-A
• chr1-155951747-C-G
• chr1-155951747-C-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001162383.2(ARHGEF2):​c.2202G>T​(p.Pro734Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,614,032 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (51 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (35 hom.)
• Consequence: ARHGEF2 NM_001162383.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.142
• Publications: 3 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 1-155951747-C-A is Benign according to our data. Variant chr1-155951747-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 777949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0126 (1923/152212) while in subpopulation AFR AF = 0.0441 (1831/41516). AF 95% confidence interval is 0.0424. There are 51 homozygotes in GnomAd4. There are 917 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 51 AR gene

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.2202G>T	p.Pro734Pro	synonymous	Exon 18 of 22	NP_001155855.1	Q92974-1
	ARHGEF2	NM_001162384.2		c.2199G>T	p.Pro733Pro	synonymous	Exon 18 of 22	NP_001155856.1	Q92974-2
	ARHGEF2	NM_001350112.2		c.2148G>T	p.Pro716Pro	synonymous	Exon 18 of 22	NP_001337041.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF2	ENST00000361247.9	TSL:1 MANE Select	c.2202G>T	p.Pro734Pro	synonymous	Exon 18 of 22	ENSP00000354837.4	Q92974-1
	ARHGEF2	ENST00000313667.8	TSL:1	c.2199G>T	p.Pro733Pro	synonymous	Exon 18 of 22	ENSP00000314787.4	Q92974-2
	ARHGEF2	ENST00000313695.11	TSL:1	c.2118G>T	p.Pro706Pro	synonymous	Exon 18 of 22	ENSP00000315325.7	Q92974-3

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1922 AN: 152094 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.0442

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.00313 AC: 786 AN: 251304 AF XY: 0.00247

Gnomad AFR exome AF: 0.0443

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00125 AC: 1831 AN: 1461820 Hom.: 35 Cov.: 33 AF XY: 0.00109 AC XY: 792 AN XY: 727212

African (AFR) AF: 0.0447 AC: 1495 AN: 33476

American (AMR) AF: 0.00148 AC: 66 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000890 AC: 99 AN: 1112004

Other (OTH) AF: 0.00262 AC: 158 AN: 60396

GnomAD4 genome AF: 0.0126 AC: 1923 AN: 152212 Hom.: 51 Cov.: 32 AF XY: 0.0123 AC XY: 917 AN XY: 74420

African (AFR) AF: 0.0441 AC: 1831 AN: 41516

American (AMR) AF: 0.00406 AC: 62 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68020

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00563 Hom.: 12

Bravo AF: 0.0141

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Neurodevelopmental disorder with midbrain and hindbrain malformations (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	11
DANN	Benign	0.57
PhyloP100		0.14
PromoterAI		-0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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: rs77345976; hg19: chr1-155921538;