16-81362609-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022041.4(GAN):​c.1084G>C​(p.Glu362Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000783 in 1,277,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 7.8e-7 ( 0 hom. )

Consequence

GAN
NM_022041.4 missense, splice_region

Scores

2
14
Splicing: ADA: 0.0008330
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.24
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16854826).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GANNM_022041.4 linkc.1084G>C p.Glu362Gln missense_variant, splice_region_variant Exon 6 of 11 ENST00000648994.2 NP_071324.1 Q9H2C0A0A0S2Z4W2B3KTC3
GANNM_001377486.1 linkc.445G>C p.Glu149Gln missense_variant, splice_region_variant Exon 5 of 10 NP_001364415.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GANENST00000648994.2 linkc.1084G>C p.Glu362Gln missense_variant, splice_region_variant Exon 6 of 11 NM_022041.4 ENSP00000497351.1 Q9H2C0

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
7.83e-7
AC:
1
AN:
1277350
Hom.:
0
Cov.:
20
AF XY:
0.00
AC XY:
0
AN XY:
644528
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00
Gnomad4 OTH exome
AF:
0.0000185
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Dec 02, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1084G>C (p.E362Q) alteration is located in exon 6 (coding exon 6) of the GAN gene. This alteration results from a G to C substitution at nucleotide position 1084, causing the glutamic acid (E) at amino acid position 362 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
19
DANN
Benign
0.97
DEOGEN2
Benign
0.28
T;T
Eigen
Benign
-0.21
Eigen_PC
Benign
-0.039
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.85
.;T
M_CAP
Benign
0.0043
T
MetaRNN
Benign
0.17
T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.27
N;N
PrimateAI
Uncertain
0.55
T
Sift4G
Benign
0.89
T;.
Polyphen
0.028
B;B
Vest4
0.32
MutPred
0.30
Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);
MVP
0.80
MPC
0.13
ClinPred
0.42
T
GERP RS
5.0
Varity_R
0.20
gMVP
0.51

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00083
dbscSNV1_RF
Benign
0.026
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-81396214; API