16-81315141-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022041.4(GAN):c.28C>T(p.Pro10Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000391 in 1,535,982 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P10R) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

GAN
NM_022041.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.38

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAN	NM_022041.4 linkuse as main transcript	c.28C>T	p.Pro10Ser	missense_variant	1/11	ENST00000648994.2
GAN	NM_001377486.1 linkuse as main transcript	c.-497C>T		5_prime_UTR_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Appris
GAN	ENST00000648994.2 linkuse as main transcript	c.28C>T	p.Pro10Ser	missense_variant	1/11	NM_022041.4	P1
GAN	ENST00000674788.1 linkuse as main transcript	n.153C>T		non_coding_transcript_exon_variant	1/3
GAN	ENST00000648349.2 linkuse as main transcript	c.28C>T	p.Pro10Ser	missense_variant, NMD_transcript_variant	1/10
GAN	ENST00000650388.1 linkuse as main transcript	c.28C>T	p.Pro10Ser	missense_variant, NMD_transcript_variant	1/9

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000361

AC:

AN:

1383878

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

684750

show subpopulations

Gnomad4 AFR exome

AF:

0.0000348

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000372

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Giant axonal neuropathy 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 30, 2023

This variant has not been reported in the literature in individuals affected with GAN-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GAN protein function. ClinVar contains an entry for this variant (Variation ID: 1922946). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 10 of the GAN protein (p.Pro10Ser). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.34

T;T

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.97

MetaRNN

Uncertain

0.72

D;D

MetaSVM

Benign

-0.63

MutationAssessor

Benign

1.3

L;L

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.94

Sift4G

Pathogenic

0.0

D;.

Polyphen

0.92

P;P

Vest4

0.49

MutPred

0.49

Gain of phosphorylation at P10 (P = 0.0269);Gain of phosphorylation at P10 (P = 0.0269);

MVP

0.94

MPC

0.23

ClinPred

0.98

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.80

gMVP

0.55

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