20-48953763-C-G

Variant names:

• chr20-48953763-C-G
• rs143570842
• NM_006420.3:c.811C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006420.3(ARFGEF2):​c.811C>G​(p.Pro271Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,614,064 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (7 hom.)
• Consequence: ARFGEF2 NM_006420.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -0.695
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009641409).
• BP6: Variant 20-48953763-C-G is Benign according to our data. Variant chr20-48953763-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128446.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00162 (247/152272) while in subpopulation NFE AF = 0.00295 (201/68034). AF 95% confidence interval is 0.00262. There are 0 homozygotes in GnomAd4. There are 114 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR,AD gene

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.811C>G	p.Pro271Ala	missense	Exon 6 of 39	NP_006411.2	Q9Y6D5
	ARFGEF2	NM_001410846.1		c.811C>G	p.Pro271Ala	missense	Exon 6 of 39	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.811C>G	p.Pro271Ala	missense	Exon 6 of 39	ENSP00000360985.4	Q9Y6D5
	ARFGEF2	ENST00000679436.1		c.811C>G	p.Pro271Ala	missense	Exon 6 of 39	ENSP00000504888.1	A0A7P0T7Z2
	ARFGEF2	ENST00000939861.1		c.811C>G	p.Pro271Ala	missense	Exon 6 of 39	ENSP00000609920.1

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 247 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00295

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00129 AC: 323 AN: 251010 AF XY: 0.00131

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00260

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00285 AC: 4169 AN: 1461792 Hom.: 7 Cov.: 32 AF XY: 0.00277 AC XY: 2013 AN XY: 727194

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86242

European-Finnish (FIN) AF: 0.000543 AC: 29 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00360 AC: 4004 AN: 1111952

Other (OTH) AF: 0.00184 AC: 111 AN: 60388

GnomAD4 genome AF: 0.00162 AC: 247 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.00153 AC XY: 114 AN XY: 74452

African (AFR) AF: 0.000578 AC: 24 AN: 41552

American (AMR) AF: 0.000131 AC: 2 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00295 AC: 201 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00222 Hom.: 0

Bravo AF: 0.00167

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00123 AC: 150

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	not specified (2)
-	-	1	ARFGEF2-related disorder (1)
-	1	-	Periventricular heterotopia with microcephaly, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.3
DANN	Benign	0.30
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.69
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.080
Sift	Benign	0.50	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.10
MVP		0.15
MPC		0.41
ClinPred		0.0027	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.012
gMVP		0.32
Mutation Taster		=95/5	polymorphism

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: rs143570842; hg19: chr20-47570300; COSMIC: COSV64213263;