chr20-49013912-C-G

Variant names:

• chr20-49013912-C-G
• rs2281582
• NM_006420.3:c.4131C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006420.3(ARFGEF2):​c.4131C>G​(p.Ile1377Met) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I1377I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARFGEF2 NM_006420.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.512
• Publications: 16 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: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARFGEF2	NM_006420.3	c.4131C>G	p.Ile1377Met	missense_variant	Exon 30 of 39	ENST00000371917.5	NP_006411.2
ARFGEF2	NM_001410846.1	c.4128C>G	p.Ile1376Met	missense_variant	Exon 30 of 39		NP_001397775.1
ARFGEF2	XM_047439832.1	c.3567C>G	p.Ile1189Met	missense_variant	Exon 28 of 37		XP_047295788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5	c.4131C>G	p.Ile1377Met	missense_variant	Exon 30 of 39	1	NM_006420.3	ENSP00000360985.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 2364

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.28	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		-0.51
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.53		Gain of MoRF binding (P = 0.122);
MVP		0.52
MPC		1.2
ClinPred		0.99	D
GERP RS		-4.5
Varity_R		0.44
gMVP		0.54
Mutation Taster		=78/22	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: rs2281582; hg19: chr20-47630449;