rs2608555

Positions:

chr16-81365030-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_022041.4(GAN):c.1293C>T(p.Tyr431=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,612,604 control chromosomes in the GnomAD database, including 43,257 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3607 hom., cov: 31)

Exomes 𝑓: 0.23 ( 39650 hom. )

Consequence

GAN
NM_022041.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.193

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 16-81365030-C-T is Benign according to our data. Variant chr16-81365030-C-T is described in ClinVar as [Benign]. Clinvar id is 129131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81365030-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.193 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAN	NM_022041.4 linkuse as main transcript	c.1293C>T	p.Tyr431=	synonymous_variant	8/11	ENST00000648994.2	NP_071324.1
GAN	NM_001377486.1 linkuse as main transcript	c.654C>T	p.Tyr218=	synonymous_variant	7/10		NP_001364415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	Appris
GAN	ENST00000648994.2 linkuse as main transcript	c.1293C>T	p.Tyr431=	synonymous_variant	8/11	NM_022041.4	ENSP00000497351	P1
GAN	ENST00000648349.2 linkuse as main transcript	c.*1001C>T		3_prime_UTR_variant, NMD_transcript_variant	7/10		ENSP00000498114
GAN	ENST00000650388.1 linkuse as main transcript	c.*650C>T		3_prime_UTR_variant, NMD_transcript_variant	6/9		ENSP00000498081

Frequencies

GnomAD3 genomes

AF:

0.211

AC:

32041

AN:

151902

Hom.:

3606

Cov.:

show subpopulations

Gnomad AFR

AF:

0.189

Gnomad AMI

AF:

0.184

Gnomad AMR

AF:

0.172

Gnomad ASJ

AF:

0.203

Gnomad EAS

AF:

0.0350

Gnomad SAS

AF:

0.147

Gnomad FIN

AF:

0.212

Gnomad MID

AF:

0.212

Gnomad NFE

AF:

0.252

Gnomad OTH

AF:

0.222

GnomAD3 exomes

AF:

0.194

AC:

48729

AN:

251396

Hom.:

5366

AF XY:

0.197

AC XY:

26795

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.188

Gnomad AMR exome

AF:

0.123

Gnomad ASJ exome

AF:

0.208

Gnomad EAS exome

AF:

0.0287

Gnomad SAS exome

AF:

0.145

Gnomad FIN exome

AF:

0.215

Gnomad NFE exome

AF:

0.250

Gnomad OTH exome

AF:

0.214

GnomAD4 exome

AF:

0.227

AC:

331134

AN:

1460584

Hom.:

39650

Cov.:

AF XY:

0.226

AC XY:

163925

AN XY:

726616

show subpopulations

Gnomad4 AFR exome

AF:

0.185

Gnomad4 AMR exome

AF:

0.128

Gnomad4 ASJ exome

AF:

0.202

Gnomad4 EAS exome

AF:

0.0417

Gnomad4 SAS exome

AF:

0.149

Gnomad4 FIN exome

AF:

0.215

Gnomad4 NFE exome

AF:

0.247

Gnomad4 OTH exome

AF:

0.211

GnomAD4 genome

AF:

0.211

AC:

32058

AN:

152020

Hom.:

3607

Cov.:

AF XY:

0.206

AC XY:

15293

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.189

Gnomad4 AMR

AF:

0.171

Gnomad4 ASJ

AF:

0.203

Gnomad4 EAS

AF:

0.0349

Gnomad4 SAS

AF:

0.147

Gnomad4 FIN

AF:

0.212

Gnomad4 NFE

AF:

0.252

Gnomad4 OTH

AF:

0.221

Alfa

AF:

0.240

Hom.:

5995

Bravo

AF:

0.203

Asia WGS

AF:

0.111

AC:

389

AN:

3478

EpiCase

AF:

0.253

EpiControl

AF:

0.258

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Giant axonal neuropathy 1

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	Oct 09, 2014	This SCV is no longer cited in the GeneReview (NBK1136). -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.98

DANN

Benign

0.25

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

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