rs778607741
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_006420.3(ARFGEF2):c.5024G>A(p.Arg1675His) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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 -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ARFGEF2 | NM_006420.3 | c.5024G>A | p.Arg1675His | missense_variant | Exon 37 of 39 | ENST00000371917.5 | NP_006411.2 | |
ARFGEF2 | NM_001410846.1 | c.5021G>A | p.Arg1674His | missense_variant | Exon 37 of 39 | NP_001397775.1 | ||
ARFGEF2 | XM_047439832.1 | c.4460G>A | p.Arg1487His | missense_variant | Exon 35 of 37 | XP_047295788.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152218Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251422Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135894
GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461836Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17AN XY: 727224
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74364
ClinVar
Submissions by phenotype
not provided Uncertain:3
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Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1675 of the ARFGEF2 protein (p.Arg1675His). This variant is present in population databases (rs778607741, gnomAD 0.01%). 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: 434292). 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. -
not specified Uncertain:1
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Inborn genetic diseases Uncertain:1
The c.5024G>A (p.R1675H) alteration is located in exon 37 (coding exon 37) of the ARFGEF2 gene. This alteration results from a G to A substitution at nucleotide position 5024, causing the arginine (R) at amino acid position 1675 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at