16-81315122-G-C

Variant names:

• chr16-81315122-G-C
• rs1028262778
• NM_022041.4:c.9G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022041.4(GAN):​c.9G>C​(p.Glu3Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: GAN NM_022041.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.463

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17600635).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAN	NM_022041.4	c.9G>C	p.Glu3Asp	missense_variant	Exon 1 of 11	ENST00000648994.2	NP_071324.1
GAN	NM_001377486.1	c.-516G>C		5_prime_UTR_variant	Exon 1 of 10		NP_001364415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAN	ENST00000648994.2	c.9G>C	p.Glu3Asp	missense_variant	Exon 1 of 11		NM_022041.4	ENSP00000497351.1
GAN	ENST00000648349.2	n.9G>C		non_coding_transcript_exon_variant	Exon 1 of 10			ENSP00000498114.1
GAN	ENST00000650388.1	n.9G>C		non_coding_transcript_exon_variant	Exon 1 of 9			ENSP00000498081.1
GAN	ENST00000674788.1	n.134G>C		non_coding_transcript_exon_variant	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151952 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151952 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74242

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.70	.;T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Pathogenic	0.94	D
Sift4G	Benign	0.084	T;.
Polyphen		0.012	B;B
Vest4		0.14
MutPred		0.091		Loss of catalytic residue at E3 (P = 0.0922);Loss of catalytic residue at E3 (P = 0.0922);
MVP		0.77
MPC		0.10
ClinPred		0.39	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.17
gMVP		0.25

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: rs1028262778; hg19: chr16-81348727;