rs77470936

chr16-81315159-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.32

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 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00978 AC: 1488 AN: 152140 Hom.: 11 Cov.: 33

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.: 20 AF XY: 0.0102 AC XY: 953 AN XY: 93194

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.: 32 AF XY: 0.0117 AC XY: 8154 AN XY: 695186

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.: 11 Cov.: 33 AF XY: 0.00943 AC XY: 702 AN XY: 74442

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.: 12

Bravo AF: 0.00988

Asia WGS AF: 0.00203 AC: 7 AN: 3464

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Giant axonal neuropathy 1 Benign:3

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	GAN: BP4, BP7, BS1, BS2 -
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 condition Benign:1

Benign, criteria provided, single submitter

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	13
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

Other links and lift over

dbSNP: rs77470936; hg19: chr16-81348764;