rs146576740

Variant names:

• chr16-81365421-C-T
• rs146576740
• NM_022041.4:c.1445C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-81365421-C-T
• chr16-81365421-C-A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_022041.4(GAN):​c.1445C>T​(p.Ala482Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,613,374 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A482T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0024 (5 hom.)
• Consequence: GAN NM_022041.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 0.796
• Publications: 9 publications found

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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.005330026).
• BP6: Variant 16-81365421-C-T is Benign according to our data. Variant chr16-81365421-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 265171.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00164 (249/151606) while in subpopulation NFE AF = 0.00286 (194/67910). AF 95% confidence interval is 0.00253. There are 0 homozygotes in GnomAd4. There are 114 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022041.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAN	NM_022041.4	MANE Select	c.1445C>T	p.Ala482Val	missense	Exon 9 of 11	NP_071324.1	A0A0S2Z4W2
	GAN	NM_001377486.1		c.806C>T	p.Ala269Val	missense	Exon 8 of 10	NP_001364415.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAN	ENST00000648994.2	MANE Select	c.1445C>T	p.Ala482Val	missense	Exon 9 of 11	ENSP00000497351.1	Q9H2C0
	GAN	ENST00000718305.1		c.1445C>T	p.Ala482Val	missense	Exon 9 of 11	ENSP00000520738.1	Q9H2C0
	GAN	ENST00000880995.1		c.1094C>T	p.Ala365Val	missense	Exon 8 of 10	ENSP00000551054.1

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 249 AN: 151488 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000364

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000395

Gnomad ASJ AF: 0.00491

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.000477

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00286

Gnomad OTH AF: 0.00289

GnomAD2 exomes AF: 0.00172 AC: 433 AN: 251492 AF XY: 0.00181

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00240

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00236 AC: 3454 AN: 1461768 Hom.: 5 Cov.: 32 AF XY: 0.00239 AC XY: 1741 AN XY: 727202

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.000805 AC: 36 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00631 AC: 165 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00101 AC: 87 AN: 86254

European-Finnish (FIN) AF: 0.000580 AC: 31 AN: 53418

Middle Eastern (MID) AF: 0.00659 AC: 38 AN: 5768

European-Non Finnish (NFE) AF: 0.00264 AC: 2940 AN: 1111896

Other (OTH) AF: 0.00245 AC: 148 AN: 60392

GnomAD4 genome AF: 0.00164 AC: 249 AN: 151606 Hom.: 0 Cov.: 30 AF XY: 0.00154 AC XY: 114 AN XY: 74040

African (AFR) AF: 0.000363 AC: 15 AN: 41320

American (AMR) AF: 0.000395 AC: 6 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00491 AC: 17 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.000419 AC: 2 AN: 4776

European-Finnish (FIN) AF: 0.000477 AC: 5 AN: 10488

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.00286 AC: 194 AN: 67910

Other (OTH) AF: 0.00286 AC: 6 AN: 2096

Alfa AF: 0.00247 Hom.: 1

Bravo AF: 0.00173

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00165 AC: 200

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00311

EpiControl AF: 0.00367

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Giant axonal neuropathy 1 (3)
-	1	1	not provided (2)
-	-	1	GAN-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.80
PrimateAI	Benign	0.30	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.19
MVP		0.58
MPC		0.12
ClinPred		0.0095	T
GERP RS		1.9
Varity_R		0.025
gMVP		0.15
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs146576740; hg19: chr16-81399026;