16-81315131-C-CA
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_022041.4(GAN):c.18_19insA(p.Val7SerfsTer3) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A6A) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Consequence
GAN
NM_022041.4 frameshift
NM_022041.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.60
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 10 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 78 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAN | NM_022041.4 | c.18_19insA | p.Val7SerfsTer3 | frameshift_variant | 1/11 | ENST00000648994.2 | |
GAN | NM_001377486.1 | c.-507_-506insA | 5_prime_UTR_variant | 1/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAN | ENST00000648994.2 | c.18_19insA | p.Val7SerfsTer3 | frameshift_variant | 1/11 | NM_022041.4 | P1 | ||
GAN | ENST00000674788.1 | n.143_144insA | non_coding_transcript_exon_variant | 1/3 | |||||
GAN | ENST00000648349.2 | c.18_19insA | p.Val7SerfsTer3 | frameshift_variant, NMD_transcript_variant | 1/10 | ||||
GAN | ENST00000650388.1 | c.18_19insA | p.Val7SerfsTer3 | frameshift_variant, NMD_transcript_variant | 1/9 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Giant axonal neuropathy 1 Pathogenic:1Uncertain:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2000 | - - |
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium Ii, University Of Miami | Jan 06, 2016 | - - |
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at