Genetic Variant GAN:p.Gly38Arg (chr16-81315225-G-C) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_022041.4(GAN):c.112G>C(p.Gly38Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,431,072 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GAN
NM_022041.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.91

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 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, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAN	NM_022041.4 link	c.112G>C	p.Gly38Arg	missense_variant	Exon 1 of 11	ENST00000648994.2	NP_071324.1
GAN	NM_001377486.1 link	c.-413G>C		5_prime_UTR_variant	Exon 1 of 10		NP_001364415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAN	ENST00000648994.2 link	c.112G>C	p.Gly38Arg	missense_variant	Exon 1 of 11		NM_022041.4	ENSP00000497351.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1431072

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

711206

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30382

American (AMR)

AF:

0.00

AC:

AN:

41614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25220

East Asian (EAS)

AF:

0.00

AC:

AN:

36574

South Asian (SAS)

AF:

0.00

AC:

AN:

82132

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5630

European-Non Finnish (NFE)

AF:

0.00000182

AC:

AN:

1098896

Other (OTH)

AF:

0.00

AC:

AN:

59052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

D;D

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.0

.;D

M_CAP

Pathogenic

1.0

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

0.11

MutationAssessor

Uncertain

2.4

M;M

PhyloP100

8.9

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

0.0

.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.

Sift4G

Benign

0.40

T;.

Vest4

0.36

ClinPred

0.98

GERP RS

4.2

PromoterAI

0.081

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.76

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

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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