16-81354686-C-G

Variant names:

• chr16-81354686-C-G
• rs201884522
• NM_022041.4:c.564C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_022041.4(GAN):​c.564C>G​(p.Asn188Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N188N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAN NM_022041.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.210
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

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

• 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.

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.564C>G	p.Asn188Lys	missense	Exon 3 of 11	NP_071324.1
	GAN	NM_001377486.1		c.-76C>G		5_prime_UTR	Exon 2 of 10	NP_001364415.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAN	ENST00000648994.2	MANE Select	c.564C>G	p.Asn188Lys	missense	Exon 3 of 11	ENSP00000497351.1
	GAN	ENST00000718305.1		c.564C>G	p.Asn188Lys	missense	Exon 3 of 11	ENSP00000520738.1
	GAN	ENST00000880995.1		c.283-2099C>G		intron	N/A	ENSP00000551054.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Giant axonal neuropathy 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.21
PrimateAI	Pathogenic	0.80	T
Sift4G	Benign	0.15	T
Polyphen		0.28	B
Vest4		0.89
MutPred		0.81		Gain of ubiquitination at N188 (P = 0.023)
MVP		0.33
MPC		0.16
ClinPred		0.36	T
GERP RS		-9.5
Varity_R		0.63
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.40		Position offset: 0

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

Other links and lift over

dbSNP: rs201884522; hg19: chr16-81388291;