rs119485088
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_022041.4(GAN):c.1456G>A(p.Glu486Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_022041.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GAN | NM_022041.4 | c.1456G>A | p.Glu486Lys | missense_variant | Exon 9 of 11 | ENST00000648994.2 | NP_071324.1 | |
GAN | NM_001377486.1 | c.817G>A | p.Glu273Lys | missense_variant | Exon 8 of 10 | NP_001364415.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151636Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251492Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135922
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461820Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727218
GnomAD4 genome AF: 0.00000659 AC: 1AN: 151636Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1AN XY: 74044
ClinVar
Submissions by phenotype
Giant axonal neuropathy 1 Pathogenic:3Uncertain:1
For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 5030). This missense change has been observed in individual(s) with giant axonal neuropathy (PMID: 11062483, 20949505). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs119485088, gnomAD 0.004%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 486 of the GAN protein (p.Glu486Lys). -
ACMG classification criteria: PS4 moderate, PM2 moderate, PM3 strong, BP4 supporting -
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Inborn genetic diseases Pathogenic:1
The p.E486K variant (also known as c.1456G>A), located in coding exon 9 of the GAN gene, results from a G to A substitution at nucleotide position 1456. The glutamic acid at codon 486 is replaced by lysine, an amino acid with similar properties. This variant was homozygous in a Tunisian family and compound heterozygous with a nonsense variant in a French family with giant axonal neuropathy (GAN) (Bomont P et al. Nat. Genet., 2000 Nov;26:370-4). Another affected individual was found to carry this alteration in trans with a microdeletion involving exons 3-11 of the GAN gene (Mahammad S et al. J. Clin. Invest., 2013 May;123:1964-75). This variant was not reported in the ExAC database, with coverage at this position. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at