16-81363860-GA-G

Position:

• chr16-81363860-GA-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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]

ACMG classification

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	Protein	UniProt
GAN	NM_022041.4	c.1157del	p.Lys386ArgfsTer3	frameshift_variant	7/11	ENST00000648994.2	NP_071324.1
GAN	NM_001377486.1	c.518del	p.Lys173ArgfsTer3	frameshift_variant	6/10		NP_001364415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAN	ENST00000648994.2	c.1157del	p.Lys386ArgfsTer3	frameshift_variant	7/11		NM_022041.4	ENSP00000497351	P1
GAN	ENST00000648349.2	c.*865del		3_prime_UTR_variant, NMD_transcript_variant	6/10			ENSP00000498114
GAN	ENST00000650388.1	c.*514del		3_prime_UTR_variant, NMD_transcript_variant	5/9			ENSP00000498081

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Giant axonal neuropathy 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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

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: rs1555511861; hg19: chr16-81397465;