NM_006420.3:c.79C>T

Variant names:

• chr20-48921968-C-T
• rs587780282
• NM_006420.3:c.79C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006420.3(ARFGEF2):​c.79C>T​(p.Pro27Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,423,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P27P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ARFGEF2 NM_006420.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.0220
• Publications: 0 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000294533 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.016365498).

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.79C>T	p.Pro27Ser	missense	Exon 1 of 39	NP_006411.2	Q9Y6D5
	ARFGEF2	NM_001410846.1		c.79C>T	p.Pro27Ser	missense	Exon 1 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.79C>T	p.Pro27Ser	missense	Exon 1 of 39	ENSP00000360985.4	Q9Y6D5
	ARFGEF2	ENST00000679436.1		c.79C>T	p.Pro27Ser	missense	Exon 1 of 39	ENSP00000504888.1	A0A7P0T7Z2
	ARFGEF2	ENST00000939861.1		c.79C>T	p.Pro27Ser	missense	Exon 1 of 39	ENSP00000609920.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000538 AC: 1 AN: 185960 AF XY: 0.0000100

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000128

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1423892 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 704812

African (AFR) AF: 0.00 AC: 0 AN: 32666

American (AMR) AF: 0.00 AC: 0 AN: 38772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25380

East Asian (EAS) AF: 0.00 AC: 0 AN: 37602

South Asian (SAS) AF: 0.00 AC: 0 AN: 81124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50382

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1093350

Other (OTH) AF: 0.00 AC: 0 AN: 58894

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.058	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-2.7	N
PhyloP100		-0.022
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	2.8	N
REVEL	Benign	0.17
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.23		Gain of phosphorylation at P27 (P = 0.0382)
MVP		0.14
MPC		0.43
ClinPred		0.12	T
GERP RS		4.6
PromoterAI		-0.061	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.15
gMVP		0.14
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587780282; hg19: chr20-47538505;