16-81365421-C-T

Variant names:

• chr16-81365421-C-T
• rs146576740
• NM_022041.4:c.1445C>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_022041.4(GAN):​c.1445C>T​(p.Ala482Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,613,374 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0024 (5 hom.)
• Consequence: GAN NM_022041.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• 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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005330026).
• BP6: Variant 16-81365421-C-T is Benign according to our data. Variant chr16-81365421-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265171.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}. Variant chr16-81365421-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00164 (249/151606) while in subpopulation NFE AF= 0.00286 (194/67910). AF 95% confidence interval is 0.00253. There are 0 homozygotes in gnomad4. There are 114 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAN	NM_022041.4	c.1445C>T	p.Ala482Val	missense_variant	Exon 9 of 11	ENST00000648994.2	NP_071324.1
GAN	NM_001377486.1	c.806C>T	p.Ala269Val	missense_variant	Exon 8 of 10		NP_001364415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAN	ENST00000648994.2	c.1445C>T	p.Ala482Val	missense_variant	Exon 9 of 11		NM_022041.4	ENSP00000497351.1

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 249 AN: 151488 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000364

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000395

Gnomad ASJ AF: 0.00491

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.000477

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00286

Gnomad OTH AF: 0.00289

GnomAD3 exomes AF: 0.00172 AC: 433 AN: 251492 Hom.: 0 AF XY: 0.00181 AC XY: 246 AN XY: 135922

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00240

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00236 AC: 3454 AN: 1461768 Hom.: 5 Cov.: 32 AF XY: 0.00239 AC XY: 1741 AN XY: 727202

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.00631

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.000580

Gnomad4 NFE exome AF: 0.00264

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00164 AC: 249 AN: 151606 Hom.: 0 Cov.: 30 AF XY: 0.00154 AC XY: 114 AN XY: 74040

Gnomad4 AFR AF: 0.000363

Gnomad4 AMR AF: 0.000395

Gnomad4 ASJ AF: 0.00491

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000419

Gnomad4 FIN AF: 0.000477

Gnomad4 NFE AF: 0.00286

Gnomad4 OTH AF: 0.00286

Alfa AF: 0.00274 Hom.: 1

Bravo AF: 0.00173

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00165 AC: 200

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00311

EpiControl AF: 0.00367

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Giant axonal neuropathy 1 Uncertain:2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Oct 02, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GAN c.1445C>T; p.Ala482Val variant (rs146576740) is reported in a family with hereditary distal motor neuropathy but did not segregate with disease (Weterman 2023). This variant is found in the general population with an overall allele frequency of 0.17% (468/282820 alleles) in the Genome Aggregation Database (v.2.1.1), with an elevated frequency of 0.58% (60/10,366 alleles) in the Ashkenazi Jewish populaiton. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.169). Based on available information, this variant is considered to be likely benign. References: Weterman MAJ et al. Pathogenic variants in three families with distal muscle involvement. Neuromuscul Disord. 2023 Jan;33(1):58-64. PMID: 36539320. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:1

Sep 11, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GAN: PM2:Supporting, BP4 -

not specified Benign:1

Jan 14, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GAN c.1445C>T (p.Ala482Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 251492 control chromosomes. The observed variant frequency is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in GAN causing Giant axonal neuropathy 1 phenotype (0.0011). To our knowledge, no occurrence of c.1445C>T in individuals affected with Giant axonal neuropathy 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 265171). Based on the evidence outlined above, the variant was classified as likely benign. -

Inborn genetic diseases Benign:1

Sep 26, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

GAN-related disorder Benign:1

May 22, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.53	.;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.0053	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Benign	0.30	T
Sift4G	Benign	0.59	T;.
Polyphen		0.0	B;B
Vest4		0.19
MVP		0.58
MPC		0.12
ClinPred		0.0095	T
GERP RS		1.9
Varity_R		0.025
gMVP		0.15

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;