rs114729625

Positions:

• chr20-48953708-C-A
• chr20-48953708-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000371917.5(ARFGEF2):​c.756C>A​(p.Asn252Lys) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N252Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARFGEF2 ENST00000371917.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.67

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ARFGEF2. . Gene score misZ 2.5971 (greater than the threshold 3.09). Trascript score misZ 4.3519 (greater than threshold 3.09). GenCC has associacion of gene with periventricular nodular heterotopia, periventricular heterotopia with microcephaly, autosomal recessive.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15032166).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARFGEF2	NM_006420.3	c.756C>A	p.Asn252Lys	missense_variant	6/39	ENST00000371917.5	NP_006411.2
ARFGEF2	NM_001410846.1	c.756C>A	p.Asn252Lys	missense_variant	6/39		NP_001397775.1
ARFGEF2	XM_047439832.1	c.192C>A	p.Asn64Lys	missense_variant	4/37		XP_047295788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5	c.756C>A	p.Asn252Lys	missense_variant	6/39	1	NM_006420.3	ENSP00000360985	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 17, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.7
DANN	Benign	0.96
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.018
Sift	Benign	0.29	T
Sift4G	Benign	0.84	T
Polyphen		0.12	B
Vest4		0.55
MutPred		0.35		Gain of ubiquitination at N252 (P = 0.0014);
MVP		0.36
MPC		0.49
ClinPred		0.34	T
GERP RS		-12
Varity_R		0.043
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs114729625; hg19: chr20-47570245;