rs558816909

Variant names:

• chr16-81315044-C-T
• rs558816909
• NM_022041.4:c.-70C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-81315044-C-T
• chr16-81315044-C-G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_022041.4(GAN):​c.-70C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000176 in 1,303,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: GAN NM_022041.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.208
• Publications: 1 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ENSG00000289067 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000395 (6/152058) while in subpopulation EAS AF = 0.00117 (6/5138). AF 95% confidence interval is 0.000508. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.-70C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_071324.1	A0A0S2Z4W2
	GAN	NM_022041.4	MANE Select	c.-70C>T		5_prime_UTR	Exon 1 of 11	NP_071324.1	A0A0S2Z4W2
	GAN	NM_001377486.1		c.-594C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_001364415.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAN	ENST00000648994.2	MANE Select	c.-70C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000497351.1	Q9H2C0
	GAN	ENST00000648994.2	MANE Select	c.-70C>T		5_prime_UTR	Exon 1 of 11	ENSP00000497351.1	Q9H2C0
	GAN	ENST00000718305.1		c.-70C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000520738.1	Q9H2C0

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151954 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: 0.00116

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000148 AC: 17 AN: 1151582 Hom.: 0 Cov.: 18 AF XY: 0.00000534 AC XY: 3 AN XY: 562094

African (AFR) AF: 0.00 AC: 0 AN: 22894

American (AMR) AF: 0.00 AC: 0 AN: 12724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16460

East Asian (EAS) AF: 0.000374 AC: 10 AN: 26718

South Asian (SAS) AF: 0.00 AC: 0 AN: 51264

European-Finnish (FIN) AF: 0.0000297 AC: 1 AN: 33670

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3264

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 937266

Other (OTH) AF: 0.000106 AC: 5 AN: 47322

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152058 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74326

African (AFR) AF: 0.00 AC: 0 AN: 41500

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00117 AC: 6 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67938

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

Asia WGS AF: 0.000579 AC: 2 AN: 3466

ClinVar

ClinVar submissions

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
BayesDel_noAF	Benign	-0.77
CADD	Benign	12
DANN	Benign	0.80
PhyloP100		0.21
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs558816909; hg19: chr16-81348649; COSMIC: COSV107550525; COSMIC: COSV107550525;