16-81365030-C-T

Variant names:

• chr16-81365030-C-T
• rs2608555
• NM_022041.4:c.1293C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022041.4(GAN):​c.1293C>T​(p.Tyr431Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,612,604 control chromosomes in the GnomAD database, including 43,257 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3607 hom., cov: 31)
  • Exomes 𝑓: 0.23 (39650 hom.)
• Consequence: GAN NM_022041.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.193

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 16-81365030-C-T is Benign according to our data. Variant chr16-81365030-C-T is described in ClinVar as [Benign]. Clinvar id is 129131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81365030-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.193 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAN	NM_022041.4	c.1293C>T	p.Tyr431Tyr	synonymous_variant	Exon 8 of 11	ENST00000648994.2	NP_071324.1
GAN	NM_001377486.1	c.654C>T	p.Tyr218Tyr	synonymous_variant	Exon 7 of 10		NP_001364415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAN	ENST00000648994.2	c.1293C>T	p.Tyr431Tyr	synonymous_variant	Exon 8 of 11		NM_022041.4	ENSP00000497351.1

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32041 AN: 151902 Hom.: 3606 Cov.: 31

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.0350

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.222

GnomAD3 exomes AF: 0.194 AC: 48729 AN: 251396 Hom.: 5366 AF XY: 0.197 AC XY: 26795 AN XY: 135868

Gnomad AFR exome AF: 0.188

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.208

Gnomad EAS exome AF: 0.0287

Gnomad SAS exome AF: 0.145

Gnomad FIN exome AF: 0.215

Gnomad NFE exome AF: 0.250

Gnomad OTH exome AF: 0.214

GnomAD4 exome AF: 0.227 AC: 331134 AN: 1460584 Hom.: 39650 Cov.: 33 AF XY: 0.226 AC XY: 163925 AN XY: 726616

Gnomad4 AFR exome AF: 0.185

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.202

Gnomad4 EAS exome AF: 0.0417

Gnomad4 SAS exome AF: 0.149

Gnomad4 FIN exome AF: 0.215

Gnomad4 NFE exome AF: 0.247

Gnomad4 OTH exome AF: 0.211

GnomAD4 genome AF: 0.211 AC: 32058 AN: 152020 Hom.: 3607 Cov.: 31 AF XY: 0.206 AC XY: 15293 AN XY: 74300

Gnomad4 AFR AF: 0.189

Gnomad4 AMR AF: 0.171

Gnomad4 ASJ AF: 0.203

Gnomad4 EAS AF: 0.0349

Gnomad4 SAS AF: 0.147

Gnomad4 FIN AF: 0.212

Gnomad4 NFE AF: 0.252

Gnomad4 OTH AF: 0.221

Alfa AF: 0.240 Hom.: 5995

Bravo AF: 0.203

Asia WGS AF: 0.111 AC: 389 AN: 3478

EpiCase AF: 0.253

EpiControl AF: 0.258

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Giant axonal neuropathy 1 Benign:4

Oct 09, 2014

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

This SCV is no longer cited in the GeneReview (NBK1136). -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.98
DANN	Benign	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: rs2608555; hg19: chr16-81398635; COSMIC: COSV73720899; COSMIC: COSV73720899;