16-81377486-C-G

Position:

chr16-81377486-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

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:10

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 -16 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].

BS2

High Homozygotes in GnomAdExome4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAN	NM_022041.4 linkuse as main transcript	c.1684C>G	p.Pro562Ala	missense_variant	11/11	ENST00000648994.2	NP_071324.1	Q9H2C0A0A0S2Z4W2B3KTC3
GAN	NM_001377486.1 linkuse as main transcript	c.1045C>G	p.Pro349Ala	missense_variant	10/10		NP_001364415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAN	ENST00000648994.2 linkuse as main transcript	c.1684C>G	p.Pro562Ala	missense_variant	11/11		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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 25, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2020	This variant is associated with the following publications: (PMID: 20981092, 21356581, 27884173, 14718689) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	GAN: BS1, BS2 -

Giant axonal neuropathy 1

Uncertain:2Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -

GAN-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2019

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