20-49017521-A-G
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_006420.3(ARFGEF2):c.4480A>G(p.Met1494Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_006420.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ARFGEF2 | NM_006420.3 | c.4480A>G | p.Met1494Val | missense_variant | Exon 33 of 39 | ENST00000371917.5 | NP_006411.2 | |
ARFGEF2 | NM_001410846.1 | c.4477A>G | p.Met1493Val | missense_variant | Exon 33 of 39 | NP_001397775.1 | ||
ARFGEF2 | XM_047439832.1 | c.3916A>G | p.Met1306Val | missense_variant | Exon 31 of 37 | XP_047295788.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000658 AC: 10AN: 152084Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251354Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135850
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461754Hom.: 0 Cov.: 33 AF XY: 0.0000179 AC XY: 13AN XY: 727162
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74408
ClinVar
Submissions by phenotype
not provided Uncertain:1
This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1494 of the ARFGEF2 protein (p.Met1494Val). This variant is present in population databases (rs200763159, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ARFGEF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 338702). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Periventricular heterotopia with microcephaly, autosomal recessive Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at