Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP2BP4

The ENST00000648994.2(GAN):c.23C>G(p.Ser8Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000981 in 1,529,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

GAN
ENST00000648994.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 3.67

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

giant axonal neuropathy 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

GAN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Trascript score misZ: -2.0288 (below the threshold of 3.09). GenCC associations: The gene is linked to giant axonal neuropathy 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.29195315).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000648994.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAN	NM_022041.4	MANE Select	c.23C>G	p.Ser8Cys	missense	Exon 1 of 11	NP_071324.1
	GAN	NM_001377486.1		c.-502C>G		5_prime_UTR	Exon 1 of 10	NP_001364415.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GAN	ENST00000648994.2	MANE Select	c.23C>G	p.Ser8Cys	missense	Exon 1 of 11	ENSP00000497351.1
GAN	ENST00000718305.1		c.23C>G	p.Ser8Cys	missense	Exon 1 of 11	ENSP00000520738.1
GAN	ENST00000648349.3		n.23C>G		non_coding_transcript_exon	Exon 1 of 10	ENSP00000498114.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000695

AC:

AN:

143874

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000167

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000102

AC:

AN:

1377338

Hom.:

Cov.:

AF XY:

0.00000881

AC XY:

AN XY:

681184

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28384

American (AMR)

AF:

0.00

AC:

AN:

34312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24206

East Asian (EAS)

AF:

0.00

AC:

AN:

31832

South Asian (SAS)

AF:

0.0000130

AC:

AN:

76834

European-Finnish (FIN)

AF:

0.0000411

AC:

AN:

48650

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4788

European-Non Finnish (NFE)

AF:

0.00000840

AC:

AN:

1071468

Other (OTH)

AF:

0.0000352

AC:

AN:

56864

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41426

American (AMR)

AF:

0.0000655

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000313

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000850

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease (1)

Giant axonal neuropathy 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.086

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.30

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.042

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.69

M_CAP

Pathogenic

0.97

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.93

PhyloP100

3.7

PrimateAI

Pathogenic

0.96

Sift4G

Benign

0.15

Polyphen

0.0

Vest4

0.16

MutPred

0.33

Loss of disorder (P = 0.0214)

MVP

0.83

MPC

0.11

ClinPred

0.40

GERP RS

4.2

PromoterAI

-0.019

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.48

gMVP

0.49

Mutation Taster

=75/25

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs587781251

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over