rs77470936

Positions:

chr16-81315159-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_022041.4(GAN):c.46C>T(p.Leu16=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0116 in 1,555,040 control chromosomes in the GnomAD database, including 154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0098 ( 11 hom., cov: 33)

Exomes 𝑓: 0.012 ( 143 hom. )

Consequence

GAN
NM_022041.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.32

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BP6

Variant 16-81315159-C-T is Benign according to our data. Variant chr16-81315159-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 320649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81315159-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00977 (1488/152248) while in subpopulation NFE AF= 0.0135 (916/67994). AF 95% confidence interval is 0.0127. There are 11 homozygotes in gnomad4. There are 702 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAN	NM_022041.4 linkuse as main transcript	c.46C>T	p.Leu16=	synonymous_variant	1/11	ENST00000648994.2	NP_071324.1
GAN	NM_001377486.1 linkuse as main transcript	c.-479C>T		5_prime_UTR_variant	1/10		NP_001364415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	Appris
GAN	ENST00000648994.2 linkuse as main transcript	c.46C>T	p.Leu16=	synonymous_variant	1/11	NM_022041.4	ENSP00000497351	P1
GAN	ENST00000674788.1 linkuse as main transcript	n.171C>T		non_coding_transcript_exon_variant	1/3
GAN	ENST00000648349.2 linkuse as main transcript	c.46C>T	p.Leu16=	synonymous_variant, NMD_transcript_variant	1/10		ENSP00000498114
GAN	ENST00000650388.1 linkuse as main transcript	c.46C>T	p.Leu16=	synonymous_variant, NMD_transcript_variant	1/9		ENSP00000498081

Frequencies

GnomAD3 genomes

AF:

0.00978

AC:

1488

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0124

Gnomad ASJ

AF:

0.0403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00765

Gnomad FIN

AF:

0.00708

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.0135

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0106

AC:

1787

AN:

169200

Hom.:

AF XY:

0.0102

AC XY:

953

AN XY:

93194

show subpopulations

Gnomad AFR exome

AF:

0.00263

Gnomad AMR exome

AF:

0.00865

Gnomad ASJ exome

AF:

0.0297

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00450

Gnomad FIN exome

AF:

0.00735

Gnomad NFE exome

AF:

0.0141

Gnomad OTH exome

AF:

0.00899

GnomAD4 exome

AF:

0.0118

AC:

16588

AN:

1402792

Hom.:

143

Cov.:

AF XY:

0.0117

AC XY:

8154

AN XY:

695186

show subpopulations

Gnomad4 AFR exome

AF:

0.00220

Gnomad4 AMR exome

AF:

0.00897

Gnomad4 ASJ exome

AF:

0.0332

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00489

Gnomad4 FIN exome

AF:

0.00681

Gnomad4 NFE exome

AF:

0.0128

Gnomad4 OTH exome

AF:

0.0123

GnomAD4 genome

AF:

0.00977

AC:

1488

AN:

152248

Hom.:

Cov.:

AF XY:

0.00943

AC XY:

702

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00243

Gnomad4 AMR

AF:

0.0124

Gnomad4 ASJ

AF:

0.0403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00787

Gnomad4 FIN

AF:

0.00708

Gnomad4 NFE

AF:

0.0135

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0134

Hom.:

Bravo

AF:

0.00988

Asia WGS

AF:

0.00203

AC:

AN:

3464

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Giant axonal neuropathy 1

Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	GAN: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

GAN-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.98

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