rs2295029

Positions:

• chr20-48951472-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_006420.3(ARFGEF2):​c.423+3A>G variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.00364 in 1,614,124 control chromosomes in the GnomAD database, including 261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (27 hom., cov: 31)
  • Exomes 𝑓: 0.0035 (234 hom.)
• Consequence: ARFGEF2 NM_006420.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9103
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.44

Genes affected

ARFGEF2 (HGNC:15853): (ADP ribosylation factor guanine nucleotide exchange factor 2) ADP-ribosylation factors (ARFs) play an important role in intracellular vesicular trafficking. The protein encoded by this gene is involved in the activation of ARFs by accelerating replacement of bound GDP with GTP and is involved in Golgi transport. It contains a Sec7 domain, which may be responsible for its guanine-nucleotide exchange activity and also brefeldin A inhibition. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 20-48951472-A-G is Benign according to our data. Variant chr20-48951472-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 128440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARFGEF2	NM_006420.3	c.423+3A>G		splice_donor_region_variant, intron_variant		ENST00000371917.5	NP_006411.2
ARFGEF2	NM_001410846.1	c.423+3A>G		splice_donor_region_variant, intron_variant			NP_001397775.1
ARFGEF2	XM_047439832.1	c.-142+3A>G		splice_donor_region_variant, intron_variant			XP_047295788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5	c.423+3A>G		splice_donor_region_variant, intron_variant		1	NM_006420.3	ENSP00000360985	P4

Frequencies

GnomAD3 genomes AF: 0.00499 AC: 759 AN: 152174 Hom.: 27 Cov.: 31

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0411

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00442

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.0150 AC: 3780 AN: 251400 Hom.: 205 AF XY: 0.0109 AC XY: 1481 AN XY: 135870

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00435

Gnomad SAS exome AF: 0.000980

Gnomad FIN exome AF: 0.00115

Gnomad NFE exome AF: 0.000281

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.00350 AC: 5111 AN: 1461832 Hom.: 234 Cov.: 32 AF XY: 0.00296 AC XY: 2156 AN XY: 727226

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.0929

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0125

Gnomad4 SAS exome AF: 0.000881

Gnomad4 FIN exome AF: 0.00101

Gnomad4 NFE exome AF: 0.000130

Gnomad4 OTH exome AF: 0.00237

GnomAD4 genome AF: 0.00500 AC: 761 AN: 152292 Hom.: 27 Cov.: 31 AF XY: 0.00542 AC XY: 404 AN XY: 74478

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.0412

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00443

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000943

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00200 Hom.: 3

Bravo AF: 0.00883

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 05, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 06, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 16, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Periventricular heterotopia with microcephaly, autosomal recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.91
dbscSNV1_RF	Pathogenic	0.72
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2295029; hg19: chr20-47568009;