rs1265285256

Variant names:

• chr16-81351588-A-C
• NM_022041.4:c.173A>C

Your query was ambiguous. Multiple possible variants found:

• chr16-81351588-A-C
• chr16-81351588-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_022041.4(GAN):​c.173A>C​(p.Lys58Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000082 in 1,219,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: GAN NM_022041.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.50

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain BTB (size 69) in uniprot entity GAN_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_022041.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAN	NM_022041.4	c.173A>C	p.Lys58Thr	missense_variant	Exon 2 of 11	ENST00000648994.2	NP_071324.1
GAN	NM_001377486.1	c.-357-2817A>C		intron_variant	Intron 1 of 9		NP_001364415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAN	ENST00000648994.2	c.173A>C	p.Lys58Thr	missense_variant	Exon 2 of 11		NM_022041.4	ENSP00000497351.1
GAN	ENST00000674788.1	n.298A>C		non_coding_transcript_exon_variant	Exon 2 of 3
GAN	ENST00000648349.2	n.168-2817A>C		intron_variant	Intron 1 of 9			ENSP00000498114.1
GAN	ENST00000650388.1	n.168-5197A>C		intron_variant	Intron 1 of 8			ENSP00000498081.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.20e-7 AC: 1 AN: 1219574 Hom.: 0 Cov.: 19 AF XY: 0.00000162 AC XY: 1 AN XY: 618540

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000112

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Pathogenic	0.92	D
Sift4G	Uncertain	0.020	D;.
Polyphen		0.98	D;D
Vest4		0.79
MutPred		0.61		Gain of phosphorylation at K58 (P = 0.0249);Gain of phosphorylation at K58 (P = 0.0249);
MVP		0.94
MPC		0.56
ClinPred		0.95	D
GERP RS		5.9
Varity_R		0.86
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-81385193;