rs1555511861
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_022041.4(GAN):c.1157del(p.Lys386ArgfsTer3) 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
GAN
NM_022041.4 frameshift
NM_022041.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.64
Genes affected
GAN (HGNC:4137): (gigaxonin) This gene encodes a member of the cytoskeletal BTB/kelch (Broad-Complex, Tramtrack and Bric a brac) repeat family. The encoded protein plays a role in neurofilament architecture and is involved in mediating the ubiquitination and degradation of some proteins. Defects in this gene are a cause of giant axonal neuropathy (GAN). [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
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 16-81363860-GA-G is Pathogenic according to our data. Variant chr16-81363860-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 465385.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAN | NM_022041.4 | c.1157del | p.Lys386ArgfsTer3 | frameshift_variant | 7/11 | ENST00000648994.2 | |
GAN | NM_001377486.1 | c.518del | p.Lys173ArgfsTer3 | frameshift_variant | 6/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAN | ENST00000648994.2 | c.1157del | p.Lys386ArgfsTer3 | frameshift_variant | 7/11 | NM_022041.4 | P1 | ||
GAN | ENST00000648349.2 | c.*865del | 3_prime_UTR_variant, NMD_transcript_variant | 6/10 | |||||
GAN | ENST00000650388.1 | c.*514del | 3_prime_UTR_variant, NMD_transcript_variant | 5/9 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Giant axonal neuropathy 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 12, 2016 | This sequence change deletes one nucleotide in exon 7 of the GAN mRNA (c.1157delA), causing a frameshift at codon 386. This creates a premature translational stop signal (p.Lys386Argfs*3) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in GAN are known to be pathogenic (PMID: 11062483). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at