16-81315131-C-CA

Position:

• chr16-81315131-C-CA

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

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. AV6A?) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAN NM_022041.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:2
• 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]

ACMG classification

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 43 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	Protein	UniProt
GAN	NM_022041.4	c.18_19insA	p.Val7SerfsTer3	frameshift_variant	1/11	ENST00000648994.2	NP_071324.1
GAN	NM_001377486.1	c.-507_-506insA		5_prime_UTR_variant	1/10		NP_001364415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAN	ENST00000648994.2	c.18_19insA	p.Val7SerfsTer3	frameshift_variant	1/11		NM_022041.4	ENSP00000497351	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			ENSP00000498114
GAN	ENST00000650388.1	c.18_19insA	p.Val7SerfsTer3	frameshift_variant, NMD_transcript_variant	1/9			ENSP00000498081

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: no assertion criteria provided

Submissions by phenotype

Giant axonal neuropathy 1 Pathogenic:1 Uncertain:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2000	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1597385624; hg19: chr16-81348736;