rs6019548

Variant names:

• chr20-48946189-A-G
• rs6019548
• NM_006420.3:c.276+4202A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006420.3(ARFGEF2):​c.276+4202A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 152,118 control chromosomes in the GnomAD database, including 5,266 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 0.25 (5266 hom., cov: 32)
• Consequence: ARFGEF2 NM_006420.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0760
• Publications: 3 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: 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.469 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.276+4202A>G		intron	N/A	NP_006411.2
	ARFGEF2	NM_001410846.1		c.276+4202A>G		intron	N/A	NP_001397775.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARFGEF2	ENST00000371917.5	TSL:1 MANE Select	c.276+4202A>G		intron	N/A	ENSP00000360985.4
	ARFGEF2	ENST00000679436.1		c.276+4202A>G		intron	N/A	ENSP00000504888.1
	ARFGEF2	ENST00000939861.1		c.276+4202A>G		intron	N/A	ENSP00000609920.1

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37399 AN: 152000 Hom.: 5261 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.364

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.273

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.272

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.246 AC: 37417 AN: 152118 Hom.: 5266 Cov.: 32 AF XY: 0.255 AC XY: 18968 AN XY: 74348

African (AFR) AF: 0.117 AC: 4853 AN: 41504

American (AMR) AF: 0.365 AC: 5570 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 861 AN: 3466

East Asian (EAS) AF: 0.485 AC: 2504 AN: 5160

South Asian (SAS) AF: 0.349 AC: 1683 AN: 4820

European-Finnish (FIN) AF: 0.273 AC: 2888 AN: 10576

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.269 AC: 18280 AN: 67992

Other (OTH) AF: 0.272 AC: 574 AN: 2114

Alfa AF: 0.265 Hom.: 2887

Bravo AF: 0.248

Asia WGS AF: 0.382 AC: 1330 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.7
DANN	Benign	0.38
PhyloP100		0.076
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: rs6019548; hg19: chr20-47562726;