chr20-48963810-A-G

Variant names:

• chr20-48963810-A-G
• rs2295031
• NM_006420.3:c.839-20A>G

Variant summary

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

The NM_006420.3(ARFGEF2):​c.839-20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.333 in 1,610,356 control chromosomes in the GnomAD database, including 91,884 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11502 hom., cov: 31)
  • Exomes 𝑓: 0.33 (80382 hom.)
• Consequence: ARFGEF2 NM_006420.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0990
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 20-48963810-A-G is Benign according to our data. Variant chr20-48963810-A-G is described in ClinVar as Benign. ClinVar VariationId is 259981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.537 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.839-20A>G		intron	N/A	NP_006411.2	Q9Y6D5
	ARFGEF2	NM_001410846.1		c.839-20A>G		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.839-20A>G		intron	N/A	ENSP00000360985.4	Q9Y6D5
	ARFGEF2	ENST00000679436.1		c.839-20A>G		intron	N/A	ENSP00000504888.1	A0A7P0T7Z2
	ARFGEF2	ENST00000939861.1		c.839-20A>G		intron	N/A	ENSP00000609920.1

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56813 AN: 151710 Hom.: 11484 Cov.: 31

Gnomad AFR AF: 0.543

Gnomad AMI AF: 0.477

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.279

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.335

Gnomad OTH AF: 0.322

GnomAD2 exomes AF: 0.310 AC: 77691 AN: 250864 AF XY: 0.307

Gnomad AFR exome AF: 0.538

Gnomad AMR exome AF: 0.264

Gnomad ASJ exome AF: 0.281

Gnomad EAS exome AF: 0.155

Gnomad FIN exome AF: 0.279

Gnomad NFE exome AF: 0.331

Gnomad OTH exome AF: 0.313

GnomAD4 exome AF: 0.328 AC: 478717 AN: 1458528 Hom.: 80382 Cov.: 31 AF XY: 0.326 AC XY: 236298 AN XY: 725766

African (AFR) AF: 0.537 AC: 17948 AN: 33408

American (AMR) AF: 0.265 AC: 11840 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 7397 AN: 26104

East Asian (EAS) AF: 0.203 AC: 8031 AN: 39656

South Asian (SAS) AF: 0.282 AC: 24319 AN: 86182

European-Finnish (FIN) AF: 0.282 AC: 15035 AN: 53336

Middle Eastern (MID) AF: 0.285 AC: 1640 AN: 5758

European-Non Finnish (NFE) AF: 0.336 AC: 373150 AN: 1109144

Other (OTH) AF: 0.321 AC: 19357 AN: 60272

GnomAD4 genome AF: 0.375 AC: 56882 AN: 151828 Hom.: 11502 Cov.: 31 AF XY: 0.366 AC XY: 27162 AN XY: 74188

African (AFR) AF: 0.542 AC: 22440 AN: 41368

American (AMR) AF: 0.276 AC: 4203 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 987 AN: 3466

East Asian (EAS) AF: 0.188 AC: 969 AN: 5156

South Asian (SAS) AF: 0.282 AC: 1352 AN: 4800

European-Finnish (FIN) AF: 0.279 AC: 2943 AN: 10544

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.335 AC: 22783 AN: 67934

Other (OTH) AF: 0.327 AC: 687 AN: 2104

Alfa AF: 0.279 Hom.: 1506

Bravo AF: 0.376

Asia WGS AF: 0.278 AC: 968 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	11
DANN	Benign	0.64
PhyloP100		0.099
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2295031; hg19: chr20-47580347; COSMIC: COSV64211863;