16-81357902-C-T

Position:

chr16-81357902-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP5BP4BS2

The NM_022041.4(GAN):c.944C>T(p.Pro315Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000202 in 1,613,632 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 2 hom. )

Consequence

GAN
NM_022041.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4

Conservation

PhyloP100: 5.72

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM1

In a repeat Kelch 1 (size 52) in uniprot entity GAN_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_022041.4

PP5

Variant 16-81357902-C-T is Pathogenic according to our data. Variant chr16-81357902-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 245843.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=2}. Variant chr16-81357902-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.3408289). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAN	NM_022041.4 linkuse as main transcript	c.944C>T	p.Pro315Leu	missense_variant	5/11	ENST00000648994.2	NP_071324.1	Q9H2C0A0A0S2Z4W2B3KTC3
GAN	NM_001377486.1 linkuse as main transcript	c.305C>T	p.Pro102Leu	missense_variant	4/10		NP_001364415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAN	ENST00000648994.2 linkuse as main transcript	c.944C>T	p.Pro315Leu	missense_variant	5/11		NM_022041.4	ENSP00000497351.1		Q9H2C0

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000756

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000139

AC:

AN:

251490

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.000202

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000211

AC:

309

AN:

1461516

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

147

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.000918

Gnomad4 NFE exome

AF:

0.000219

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000112

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000756

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000118

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Giant axonal neuropathy 1

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The GAN c.944C>T (p.Pro315Leu) missense variant has been reported in two studies in which it is found in a compound heterozygous state in two patients with giant axonal neuropathy, one with a missense variant on the second allele, and one with a frameshift variant (Bruno et al. 2004; Houlden et al. 2007). The p.Pro315Leu variant was also found in a heterozygous state in one of the parents diagnosed with mild multiple sclerosis. The p.Pro315Leu variant was absent from 100 controls but is reported at a frequency of 0.000907 in the European (Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Pro315Leu variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for giant axonal neuropathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 315 of the GAN protein (p.Pro315Leu). This variant is present in population databases (rs144486241, gnomAD 0.07%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with giant axonal neuropathy (PMID: 14718689, 17578852; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 245843). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GAN protein function with a negative predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 24, 2021

The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17256086, 17578852, 14718689, 21356581, 23890932) -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2022

The p.P315L variant (also known as c.944C>T), located in coding exon 5 of the GAN gene, results from a C to T substitution at nucleotide position 944. The proline at codon 315 is replaced by leucine, an amino acid with similar properties. In one individual with giant axonal neuropathy, this alteration was detected in trans with a frameshift alteration in GAN (Houlden H et al. J Neurol Neurosurg Psychiatry, 2007 Nov;78:1267-70). This alteration was also detected as compound heterozygous with a missense alteration in GAN In another individual with giant axonal neuropathy; however, the phase of the variants was unknown (Bruno C et al. Neurology, 2004 Jan;62:13-6). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Giant axonal neuropathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Neurogenomics Lab, Neuroscience Institute, University Of Cape Town

May 22, 2024

PM2_supporting: the highest population allele frequency in gnomAD v4.0 is 0.0008910 (0.089%; 57/63974 alleles in European Finnish population) and in gnomAD v3.1.2 is 0.0007556 (0.076%; 1/10588 alleles in European Finnish population) and the variant is absent from an internal database of 1074 alleles. PS4_supporting: variant identified in 2 unrelated probands with consistent phenotype for disorder (PMID 14718689, PMID 17578852). PP3 not met: REVEL score is 0.49. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;T

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

.;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.34

T;T

MetaSVM

Uncertain

-0.15

MutationAssessor

Uncertain

2.7

M;M

PrimateAI

Uncertain

0.71

Sift4G

Benign

0.065

T;.

Polyphen

0.81

P;P

Vest4

0.89

MVP

0.92

MPC

0.18

ClinPred

0.32

GERP RS

5.9

Varity_R

0.40

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over