rs730882200

Positions:

• chr20-48953604-T-TC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006420.3(ARFGEF2):​c.656dup​(p.Val220CysfsTer35) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARFGEF2 NM_006420.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.75

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-48953604-T-TC is Pathogenic according to our data. Variant chr20-48953604-T-TC is described in ClinVar as [Pathogenic]. Clinvar id is 183282.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARFGEF2	NM_006420.3	c.656dup	p.Val220CysfsTer35	frameshift_variant	6/39	ENST00000371917.5	NP_006411.2
ARFGEF2	NM_001410846.1	c.656dup	p.Val220CysfsTer35	frameshift_variant	6/39		NP_001397775.1
ARFGEF2	XM_047439832.1	c.92dup	p.Val32CysfsTer35	frameshift_variant	4/37		XP_047295788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5	c.656dup	p.Val220CysfsTer35	frameshift_variant	6/39	1	NM_006420.3	ENSP00000360985	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hydrocephalus;C0036572:Seizure;C0557874:Global developmental delay Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 01, 2014

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 10, 2015

The c.656dupC variant in the ARFGEF2 gene has not been reported previously as a pathogenic variant nor as a benign polymorphism, to our knowledge. The c.656dupC duplication causes a frameshiftstarting with codon Valine 220, changes this amino acid to a Cysteine residue and creates a premature Stopcodon at position 35 of the new reading frame, denoted p.Val220CysfsX35. This variant is predicted tocause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.The c.656dupC variant was not observed in approximately 6,500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant inthese populations. We interpret c.656dupC as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs730882200; hg19: chr20-47570141;