chr16-81356881-A-G

Position:

chr16-81356881-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_022041.4(GAN):c.730A>G(p.Ile244Val) variant causes a missense change. The variant allele was found at a frequency of 0.000814 in 1,613,890 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00084 ( 4 hom. )

Consequence

GAN
NM_022041.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 5.04

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035799414).

BP6

Variant 16-81356881-A-G is Benign according to our data. Variant chr16-81356881-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157527.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chr16-81356881-A-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAN	NM_022041.4 linkuse as main transcript	c.730A>G	p.Ile244Val	missense_variant	4/11	ENST00000648994.2	NP_071324.1	Q9H2C0A0A0S2Z4W2B3KTC3
GAN	NM_001377486.1 linkuse as main transcript	c.91A>G	p.Ile31Val	missense_variant	3/10		NP_001364415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAN	ENST00000648994.2 linkuse as main transcript	c.730A>G	p.Ile244Val	missense_variant	4/11		NM_022041.4	ENSP00000497351.1		Q9H2C0

Frequencies

GnomAD3 genomes

AF:

0.000539

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000911

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000585

AC:

147

AN:

251490

Hom.:

AF XY:

0.000581

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000751

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000905

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.000843

AC:

1232

AN:

1461638

Hom.:

Cov.:

AF XY:

0.000791

AC XY:

575

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000661

Gnomad4 FIN exome

AF:

0.000300

Gnomad4 NFE exome

AF:

0.000971

Gnomad4 OTH exome

AF:

0.000696

GnomAD4 genome

AF:

0.000539

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000911

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000853

Hom.:

Bravo

AF:

0.000472

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000634

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00131

EpiControl

AF:

0.00166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Giant axonal neuropathy 1

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2024	See Variant Classification Assertion Criteria. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2017	- -

Charcot-Marie-Tooth disease

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Dept. of Medical Genetics, Telemark Hospital Trust, Telemark Hospital Trust

Nov 01, 2013

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

T;T

Eigen

Benign

-0.10

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.82

.;T

M_CAP

Benign

0.0033

MetaRNN

Benign

0.036

T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

-0.34

N;N

PrimateAI

Uncertain

0.57

Sift4G

Benign

0.98

T;.

Polyphen

0.0

B;B

Vest4

0.38

MVP

0.55

MPC

0.096

ClinPred

0.030

GERP RS

5.8

Varity_R

0.61

gMVP

0.17

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