16-81362570-C-G

Variant names:

• chr16-81362570-C-G
• rs374004725
• NM_022041.4:c.1045C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022041.4(GAN):​c.1045C>G​(p.Pro349Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,454,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: GAN NM_022041.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.16

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAN	NM_022041.4	c.1045C>G	p.Pro349Ala	missense_variant	Exon 6 of 11	ENST00000648994.2	NP_071324.1
GAN	NM_001377486.1	c.406C>G	p.Pro136Ala	missense_variant	Exon 5 of 10		NP_001364415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAN	ENST00000648994.2	c.1045C>G	p.Pro349Ala	missense_variant	Exon 6 of 11		NM_022041.4	ENSP00000497351.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454326 Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 2 AN XY: 724004

Gnomad4 AFR exome AF: 0.0000901

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: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Giant axonal neuropathy 1 Uncertain:1

Jul 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GAN-related conditions. ClinVar contains an entry for this variant (Variation ID: 582736). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 349 of the GAN protein (p.Pro349Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	0.0075	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.86	.;D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	1.9	L;L
PrimateAI	Uncertain	0.60	T
Sift4G	Uncertain	0.040	D;.
Polyphen		1.0	D;D
Vest4		0.59
MutPred		0.74		Loss of disorder (P = 0.0925);Loss of disorder (P = 0.0925);
MVP		0.95
MPC		0.34
ClinPred		0.85	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.73

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

Other links and lift over

dbSNP: rs374004725; hg19: chr16-81396175;