16-81377486-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_022041.4(GAN):c.1684C>G(p.Pro562Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00473 in 1,614,106 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0048 ( 25 hom. )

Consequence

GAN
NM_022041.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2B:11

Conservation

PhyloP100: 6.08

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010434002).

BP6

Variant 16-81377486-C-G is Benign according to our data. Variant chr16-81377486-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 374635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81377486-C-G is described in Lovd as [Likely_benign]. Variant chr16-81377486-C-G is described in Lovd as [Pathogenic]. Variant chr16-81377486-C-G is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00378 (576/152350) while in subpopulation NFE AF= 0.00557 (379/68034). AF 95% confidence interval is 0.00511. There are 0 homozygotes in gnomad4. There are 256 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAN	NM_022041.4 link	c.1684C>G	p.Pro562Ala	missense_variant	Exon 11 of 11	ENST00000648994.2	NP_071324.1	Q9H2C0A0A0S2Z4W2B3KTC3
GAN	NM_001377486.1 link	c.1045C>G	p.Pro349Ala	missense_variant	Exon 10 of 10		NP_001364415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAN	ENST00000648994.2 link	c.1684C>G	p.Pro562Ala	missense_variant	Exon 11 of 11		NM_022041.4	ENSP00000497351.1		Q9H2C0

Frequencies

GnomAD3 genomes

AF:

0.00378

AC:

576

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00227

Gnomad FIN

AF:

0.00828

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00557

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00482

AC:

1212

AN:

251302

Hom.:

AF XY:

0.00523

AC XY:

711

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00220

Gnomad ASJ exome

AF:

0.00516

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00385

Gnomad FIN exome

AF:

0.0101

Gnomad NFE exome

AF:

0.00620

Gnomad OTH exome

AF:

0.00489

GnomAD4 exome

AF:

0.00483

AC:

7065

AN:

1461756

Hom.:

Cov.:

AF XY:

0.00485

AC XY:

3525

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.00224

Gnomad4 ASJ exome

AF:

0.00520

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00383

Gnomad4 FIN exome

AF:

0.0103

Gnomad4 NFE exome

AF:

0.00511

Gnomad4 OTH exome

AF:

0.00339

GnomAD4 genome

AF:

0.00378

AC:

576

AN:

152350

Hom.:

Cov.:

AF XY:

0.00344

AC XY:

256

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.000794

Gnomad4 AMR

AF:

0.00176

Gnomad4 ASJ

AF:

0.00835

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00828

Gnomad4 NFE

AF:

0.00557

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00483

Hom.:

Bravo

AF:

0.00314

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00453

AC:

ExAC

AF:

0.00492

AC:

597

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00469

EpiControl

AF:

0.00593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:2Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 25, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 31, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 20981092, 21356581, 27884173, 14718689) -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GAN: BS1, BS2 -

Giant axonal neuropathy 1

Uncertain:2Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 01, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

GAN-related disorder

Benign:1

Apr 17, 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

0.086

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;T

Eigen

Benign

-0.12

Eigen_PC

Benign

0.045

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

.;T

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.81

L;L

PrimateAI

Pathogenic

0.80

Sift4G

Benign

0.27

T;.

Polyphen

0.18

B;B

Vest4

0.73

MVP

0.83

MPC

0.22

ClinPred

0.012

GERP RS

5.5

Varity_R

0.38

gMVP

0.49

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over