Genetic Variant NM_022041.4:c.601C>G (chr16-81354723-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_022041.4(GAN):c.601C>G(p.Arg201Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,449,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R201Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GAN
NM_022041.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.70

Publications

0 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 4 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.802

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAN	NM_022041.4 link	c.601C>G	p.Arg201Gly	missense_variant	Exon 3 of 11	ENST00000648994.2	NP_071324.1	Q9H2C0A0A0S2Z4W2B3KTC3
GAN	NM_001377486.1 link	c.-39C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 10		NP_001364415.1
GAN	NM_001377486.1 link	c.-39C>G		5_prime_UTR_variant	Exon 2 of 10		NP_001364415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAN	ENST00000648994.2 link	c.601C>G	p.Arg201Gly	missense_variant	Exon 3 of 11		NM_022041.4	ENSP00000497351.1		Q9H2C0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1449840

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722158

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33228

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26052

East Asian (EAS)

AF:

0.00

AC:

AN:

39636

South Asian (SAS)

AF:

0.00

AC:

AN:

85940

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00000272

AC:

AN:

1101076

Other (OTH)

AF:

0.00

AC:

AN:

60036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;D

Eigen

Pathogenic

0.68

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

.;D

M_CAP

Benign

0.024

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Uncertain

-0.26

MutationAssessor

Uncertain

2.7

M;M

PhyloP100

3.7

PrimateAI

Uncertain

0.74

Sift4G

Uncertain

0.016

D;.

Polyphen

0.97

D;D

Vest4

0.89

MutPred

0.69

Loss of MoRF binding (P = 0.0183);Loss of MoRF binding (P = 0.0183);

MVP

0.91

MPC

0.59

ClinPred

0.93

GERP RS

5.8

Varity_R

0.88

gMVP

0.69

Mutation Taster

=17/83

disease causing

(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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over