rs587779384

Variant names:

• chr16-81362609-G-A
• rs587779384
• NM_022041.4:c.1084G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-81362609-G-A
• chr16-81362609-G-C
• chr16-81362609-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_022041.4(GAN):​c.1084G>A​(p.Glu362Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000117 in 1,277,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E362Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GAN NM_022041.4 missense, splice_region
• Scores: Splicing: ADA: 0.002237
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 5.24
• Publications: 1 publications found

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]

GAN Gene-Disease associations (from GenCC):

• giant axonal neuropathy 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a repeat Kelch 2 (size 47) in uniprot entity GAN_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_022041.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Trascript score misZ: -2.0288 (below the threshold of 3.09). GenCC associations: The gene is linked to giant axonal neuropathy 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2375308).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022041.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAN	NM_022041.4	MANE Select	c.1084G>A	p.Glu362Lys	missense splice_region	Exon 6 of 11	NP_071324.1	A0A0S2Z4W2
	GAN	NM_001377486.1		c.445G>A	p.Glu149Lys	missense splice_region	Exon 5 of 10	NP_001364415.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAN	ENST00000648994.2	MANE Select	c.1084G>A	p.Glu362Lys	missense splice_region	Exon 6 of 11	ENSP00000497351.1	Q9H2C0
	GAN	ENST00000718305.1		c.1084G>A	p.Glu362Lys	missense splice_region	Exon 6 of 11	ENSP00000520738.1	Q9H2C0
	GAN	ENST00000880995.1		c.733G>A	p.Glu245Lys	missense splice_region	Exon 5 of 10	ENSP00000551054.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251470 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 15 AN: 1277348 Hom.: 0 Cov.: 20 AF XY: 0.00000465 AC XY: 3 AN XY: 644528

African (AFR) AF: 0.00 AC: 0 AN: 30130

American (AMR) AF: 0.00 AC: 0 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25026

East Asian (EAS) AF: 0.00 AC: 0 AN: 38906

South Asian (SAS) AF: 0.00 AC: 0 AN: 82486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5434

European-Non Finnish (NFE) AF: 0.0000138 AC: 13 AN: 943394

Other (OTH) AF: 0.0000369 AC: 2 AN: 54140

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease (1)
-	1	-	Giant axonal neuropathy 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.087
Eigen_PC	Benign	0.041
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	-0.055	N
PhyloP100		5.2
PrimateAI	Uncertain	0.66	T
Sift4G	Benign	0.12	T
Polyphen		0.15	B
Vest4		0.72
MutPred		0.42		Gain of ubiquitination at E362 (P = 0.023)
MVP		0.74
MPC		0.19
ClinPred		0.40	T
GERP RS		5.0
Varity_R		0.24
gMVP		0.61
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0022
dbscSNV1_RF	Benign	0.018
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

Other links and lift over

dbSNP: rs587779384; hg19: chr16-81396214; COSMIC: COSV73721485; COSMIC: COSV73721485;