NM_022041.4:c.1456G>C

Variant names:

• chr16-81365432-G-C
• rs119485088
• NM_022041.4:c.1456G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM2 PM5 PP2 BP4_Moderate

The NM_022041.4(GAN):​c.1456G>C​(p.Glu486Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E486K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: GAN NM_022041.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.65
• Publications: 10 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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-81365432-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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=0.19356102).

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.1456G>C	p.Glu486Gln	missense	Exon 9 of 11	NP_071324.1	A0A0S2Z4W2
	GAN	NM_001377486.1		c.817G>C	p.Glu273Gln	missense	Exon 8 of 10	NP_001364415.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAN	ENST00000648994.2	MANE Select	c.1456G>C	p.Glu486Gln	missense	Exon 9 of 11	ENSP00000497351.1	Q9H2C0
	GAN	ENST00000718305.1		c.1456G>C	p.Glu486Gln	missense	Exon 9 of 11	ENSP00000520738.1	Q9H2C0
	GAN	ENST00000880995.1		c.1105G>C	p.Glu369Gln	missense	Exon 8 of 10	ENSP00000551054.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251492 AF XY: 0.00000736

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.046
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
PhyloP100		7.7
PrimateAI	Uncertain	0.56	T
Sift4G	Benign	0.72	T
Polyphen		0.044	B
Vest4		0.53
MVP		0.85
MPC		0.12
ClinPred		0.94	D
GERP RS		5.7
Varity_R		0.14
gMVP		0.40

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

Other links and lift over

dbSNP: rs119485088; hg19: chr16-81399037;