rs77470936

Variant names:

• chr16-81315159-C-T
• rs77470936
• NM_022041.4:c.46C>T
• GAN p.Leu16Leu

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001377486.1(GAN):​c.-479C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0116 in 1,555,040 control chromosomes in the GnomAD database, including 154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (11 hom., cov: 33)
  • Exomes 𝑓: 0.012 (143 hom.)
• Consequence: GAN NM_001377486.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.32
• 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, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 16-81315159-C-T is Benign according to our data. Variant chr16-81315159-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 320649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00977 (1488/152248) while in subpopulation NFE AF = 0.0135 (916/67994). AF 95% confidence interval is 0.0127. There are 11 homozygotes in GnomAd4. There are 702 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377486.1. 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.46C>T	p.Leu16Leu	synonymous	Exon 1 of 11	NP_071324.1	A0A0S2Z4W2
	GAN	NM_001377486.1		c.-479C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_001364415.1
	GAN	NM_001377486.1		c.-479C>T		5_prime_UTR	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.46C>T	p.Leu16Leu	synonymous	Exon 1 of 11	ENSP00000497351.1	Q9H2C0
	GAN	ENST00000718305.1		c.46C>T	p.Leu16Leu	synonymous	Exon 1 of 11	ENSP00000520738.1	Q9H2C0
	GAN	ENST00000880995.1		c.46C>T	p.Leu16Leu	synonymous	Exon 1 of 10	ENSP00000551054.1

Frequencies

GnomAD3 genomes AF: 0.00978 AC: 1488 AN: 152140 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.0403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00765

Gnomad FIN AF: 0.00708

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0106 AC: 1787 AN: 169200 AF XY: 0.0102

Gnomad AFR exome AF: 0.00263

Gnomad AMR exome AF: 0.00865

Gnomad ASJ exome AF: 0.0297

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00735

Gnomad NFE exome AF: 0.0141

Gnomad OTH exome AF: 0.00899

GnomAD4 exome AF: 0.0118 AC: 16588 AN: 1402792 Hom.: 143 Cov.: 32 AF XY: 0.0117 AC XY: 8154 AN XY: 695186

African (AFR) AF: 0.00220 AC: 65 AN: 29612

American (AMR) AF: 0.00897 AC: 335 AN: 37344

Ashkenazi Jewish (ASJ) AF: 0.0332 AC: 821 AN: 24712

East Asian (EAS) AF: 0.00 AC: 0 AN: 34238

South Asian (SAS) AF: 0.00489 AC: 386 AN: 78860

European-Finnish (FIN) AF: 0.00681 AC: 339 AN: 49746

Middle Eastern (MID) AF: 0.00693 AC: 37 AN: 5342

European-Non Finnish (NFE) AF: 0.0128 AC: 13893 AN: 1084948

Other (OTH) AF: 0.0123 AC: 712 AN: 57990

GnomAD4 genome AF: 0.00977 AC: 1488 AN: 152248 Hom.: 11 Cov.: 33 AF XY: 0.00943 AC XY: 702 AN XY: 74442

African (AFR) AF: 0.00243 AC: 101 AN: 41572

American (AMR) AF: 0.0124 AC: 190 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0403 AC: 140 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00787 AC: 38 AN: 4830

European-Finnish (FIN) AF: 0.00708 AC: 75 AN: 10592

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0135 AC: 916 AN: 67994

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.0134 Hom.: 12

Bravo AF: 0.00988

Asia WGS AF: 0.00203 AC: 7 AN: 3464

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Giant axonal neuropathy 1 (3)
-	-	3	not provided (3)
-	-	1	GAN-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	13
DANN	Uncertain	0.98
PhyloP100		4.3
PromoterAI		0.018	Neutral
Mutation Taster		=87/13	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs77470936;

hg19: chr16-81348764;