NM_022041.4:c.730A>C

Variant names:

• chr16-81356881-A-C
• rs200749953
• NM_022041.4:c.730A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_022041.4(GAN):​c.730A>C​(p.Ile244Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 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. I244V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GAN NM_022041.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.04
• Publications: 2 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 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20071346).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAN	NM_022041.4	c.730A>C	p.Ile244Leu	missense_variant	Exon 4 of 11	ENST00000648994.2	NP_071324.1
GAN	NM_001377486.1	c.91A>C	p.Ile31Leu	missense_variant	Exon 3 of 10		NP_001364415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAN	ENST00000648994.2	c.730A>C	p.Ile244Leu	missense_variant	Exon 4 of 11		NM_022041.4	ENSP00000497351.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 4

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.025
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.55	N;N
PhyloP100		5.0
PrimateAI	Uncertain	0.66	T
Sift4G	Benign	0.29	T;.
Polyphen		0.0010	B;B
Vest4		0.57
MutPred		0.27		Loss of methylation at K246 (P = 0.0483);Loss of methylation at K246 (P = 0.0483);
MVP		0.61
MPC		0.12
ClinPred		0.51	D
GERP RS		5.8
Varity_R		0.86
gMVP		0.39

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: rs200749953; hg19: chr16-81390486;