20-49017510-G-C

Variant names:

• chr20-49017510-G-C
• NM_006420.3:c.4469G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006420.3(ARFGEF2):​c.4469G>C​(p.Arg1490Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARFGEF2 NM_006420.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.99

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24351126).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARFGEF2	NM_006420.3	c.4469G>C	p.Arg1490Thr	missense_variant	Exon 33 of 39	ENST00000371917.5	NP_006411.2
ARFGEF2	NM_001410846.1	c.4466G>C	p.Arg1489Thr	missense_variant	Exon 33 of 39		NP_001397775.1
ARFGEF2	XM_047439832.1	c.3905G>C	p.Arg1302Thr	missense_variant	Exon 31 of 37		XP_047295788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5	c.4469G>C	p.Arg1490Thr	missense_variant	Exon 33 of 39	1	NM_006420.3	ENSP00000360985.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4469G>C (p.R1490T) alteration is located in exon 33 (coding exon 33) of the ARFGEF2 gene. This alteration results from a G to C substitution at nucleotide position 4469, causing the arginine (R) at amino acid position 1490 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Benign	0.42	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.097
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	L
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.21
Sift	Uncertain	0.026	D
Sift4G	Benign	0.11	T
Polyphen		0.0090	B
Vest4		0.53
MutPred		0.47		Gain of glycosylation at R1490 (P = 0.0502);
MVP		0.65
MPC		0.64
ClinPred		0.96	D
GERP RS		1.5
Varity_R		0.24
gMVP		0.52

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-47634047;