rs201884522

Positions:

• chr16-81354686-C-G
• chr16-81354686-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_022041.4(GAN):​c.564C>G​(p.Asn188Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N188N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAN NM_022041.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.210

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.

• PM1: In a domain BACK (size 102) in uniprot entity GAN_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_022041.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAN	NM_022041.4	c.564C>G	p.Asn188Lys	missense_variant	3/11	ENST00000648994.2
GAN	NM_001377486.1	c.-76C>G		5_prime_UTR_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAN	ENST00000648994.2	c.564C>G	p.Asn188Lys	missense_variant	3/11		NM_022041.4	P1
GAN	ENST00000674788.1	n.689C>G		non_coding_transcript_exon_variant	3/3
GAN	ENST00000648349.2	c.*272C>G		3_prime_UTR_variant, NMD_transcript_variant	2/10
GAN	ENST00000650388.1	c.168-2099C>G		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Giant axonal neuropathy 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 24, 2018

This sequence change replaces asparagine with lysine at codon 188 of the GAN protein (p.Asn188Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with GAN-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Uncertain	0.76	D;D
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.60	D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	T
Sift4G	Benign	0.15	T;.
Polyphen		0.28	B;B
Vest4		0.89
MutPred		0.81		Gain of ubiquitination at N188 (P = 0.023);Gain of ubiquitination at N188 (P = 0.023);
MVP		0.33
MPC		0.16
ClinPred		0.36	T
GERP RS		-9.5
Varity_R		0.63
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.40		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201884522; hg19: chr16-81388291;