rs4810905

Variant names:

• chr20-48988288-G-A
• rs4810905
• NM_006420.3:c.2277-16G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-48988288-G-A
• chr20-48988288-G-C

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.2277-16G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 1,606,098 control chromosomes in the GnomAD database, including 64,413 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5178 hom., cov: 32)
  • Exomes 𝑓: 0.28 (59235 hom.)
• Consequence: ARFGEF2 NM_006420.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.170
• Publications: 12 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=-0.84).
• BP6: Variant 20-48988288-G-A is Benign according to our data. Variant chr20-48988288-G-A is described in ClinVar as Benign. ClinVar VariationId is 259979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.456 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.2277-16G>A		intron	N/A	NP_006411.2	Q9Y6D5
	ARFGEF2	NM_001410846.1		c.2274-16G>A		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.2277-16G>A		intron	N/A	ENSP00000360985.4	Q9Y6D5
	ARFGEF2	ENST00000679436.1		c.2274-16G>A		intron	N/A	ENSP00000504888.1	A0A7P0T7Z2
	ARFGEF2	ENST00000939861.1		c.2271-16G>A		intron	N/A	ENSP00000609920.1

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37079 AN: 151804 Hom.: 5172 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.272

GnomAD2 exomes AF: 0.310 AC: 77345 AN: 249300 AF XY: 0.308

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.439

Gnomad ASJ exome AF: 0.271

Gnomad EAS exome AF: 0.489

Gnomad FIN exome AF: 0.265

Gnomad NFE exome AF: 0.271

Gnomad OTH exome AF: 0.286

GnomAD4 exome AF: 0.279 AC: 405859 AN: 1454176 Hom.: 59235 Cov.: 30 AF XY: 0.282 AC XY: 204155 AN XY: 723816

African (AFR) AF: 0.110 AC: 3675 AN: 33360

American (AMR) AF: 0.424 AC: 18930 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 6993 AN: 26072

East Asian (EAS) AF: 0.450 AC: 17834 AN: 39610

South Asian (SAS) AF: 0.349 AC: 30017 AN: 86030

European-Finnish (FIN) AF: 0.267 AC: 13962 AN: 52294

Middle Eastern (MID) AF: 0.256 AC: 1474 AN: 5750

European-Non Finnish (NFE) AF: 0.268 AC: 295940 AN: 1106316

Other (OTH) AF: 0.283 AC: 17034 AN: 60140

GnomAD4 genome AF: 0.244 AC: 37096 AN: 151922 Hom.: 5178 Cov.: 32 AF XY: 0.253 AC XY: 18758 AN XY: 74232

African (AFR) AF: 0.116 AC: 4818 AN: 41426

American (AMR) AF: 0.364 AC: 5552 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 856 AN: 3464

East Asian (EAS) AF: 0.472 AC: 2436 AN: 5162

South Asian (SAS) AF: 0.349 AC: 1683 AN: 4824

European-Finnish (FIN) AF: 0.261 AC: 2750 AN: 10530

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.268 AC: 18224 AN: 67946

Other (OTH) AF: 0.272 AC: 572 AN: 2106

Alfa AF: 0.218 Hom.: 1113

Bravo AF: 0.247

Asia WGS AF: 0.374 AC: 1301 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)
-	-	1	Periventricular heterotopia with microcephaly, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.9
DANN	Benign	0.39
PhyloP100		-0.17
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: rs4810905; hg19: chr20-47604825; COSMIC: COSV64211308;