rs146576740

Positions:

• chr16-81365421-C-A
• chr16-81365421-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022041.4(GAN):​c.1445C>A​(p.Ala482Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/18 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. A482V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: GAN NM_022041.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.796

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047978133).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAN	NM_022041.4	c.1445C>A	p.Ala482Asp	missense_variant	9/11	ENST00000648994.2
GAN	NM_001377486.1	c.806C>A	p.Ala269Asp	missense_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAN	ENST00000648994.2	c.1445C>A	p.Ala482Asp	missense_variant	9/11		NM_022041.4	P1
GAN	ENST00000567335.1	n.3C>A		non_coding_transcript_exon_variant	1/2	3
GAN	ENST00000648349.2	c.*1153C>A		3_prime_UTR_variant, NMD_transcript_variant	8/10
GAN	ENST00000650388.1	c.*802C>A		3_prime_UTR_variant, NMD_transcript_variant	7/9

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251492 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135922

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Benign	0.64
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.76	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.048	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.35	T
Sift4G	Benign	0.29	T;.
Polyphen		0.0080	B;B
Vest4		0.28
MutPred		0.35		Gain of disorder (P = 0.0933);Gain of disorder (P = 0.0933);
MVP		0.74
MPC		0.19
ClinPred		0.11	T
GERP RS		1.9
Varity_R		0.11
gMVP		0.34

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

LitVar

Other links and lift over

dbSNP: rs146576740; hg19: chr16-81399026;