rs2295029

Variant names:

• chr20-48951472-A-G
• rs2295029
• NM_006420.3:c.423+3A>G

Variant summary

Our verdict is Benign. The variant received -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 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. 2/3 splice prediction tools predict no significant impact on normal splicing. 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_region, intron
• Scores: Splicing: ADA: 0.9103
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.44
• Publications: 6 publications found

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]

ARFGEF2 Gene-Disease associations (from GenCC):

• periventricular heterotopia with microcephaly, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006420.3. 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
	ARFGEF2	NM_006420.3	MANE Select	c.423+3A>G		splice_region intron	N/A	NP_006411.2	Q9Y6D5
	ARFGEF2	NM_001410846.1		c.423+3A>G		splice_region intron	N/A	NP_001397775.1	A0A7P0T7Z2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARFGEF2	ENST00000371917.5	TSL:1 MANE Select	c.423+3A>G		splice_region intron	N/A	ENSP00000360985.4	Q9Y6D5
	ARFGEF2	ENST00000679436.1		c.423+3A>G		splice_region intron	N/A	ENSP00000504888.1	A0A7P0T7Z2
	ARFGEF2	ENST00000939861.1		c.423+3A>G		splice_region intron	N/A	ENSP00000609920.1

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

GnomAD2 exomes AF: 0.0150 AC: 3780 AN: 251400 AF XY: 0.0109

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 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

African (AFR) AF: 0.00108 AC: 36 AN: 33478

American (AMR) AF: 0.0929 AC: 4157 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0125 AC: 498 AN: 39696

South Asian (SAS) AF: 0.000881 AC: 76 AN: 86256

European-Finnish (FIN) AF: 0.00101 AC: 54 AN: 53412

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000130 AC: 145 AN: 1111970

Other (OTH) AF: 0.00237 AC: 143 AN: 60392

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

African (AFR) AF: 0.00130 AC: 54 AN: 41554

American (AMR) AF: 0.0412 AC: 630 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00443 AC: 23 AN: 5192

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.000943 AC: 10 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68032

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Periventricular heterotopia with microcephaly, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Benign	0.84
PhyloP100		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=79/21	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2295029; hg19: chr20-47568009;