rs77078389

Variant names:

• chr16-81351535-C-G
• rs77078389
• NM_022041.4:c.168-48C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022041.4(GAN):​c.168-48C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00853 in 802,626 control chromosomes in the GnomAD database, including 175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0091 (151 hom.)
• Consequence: GAN NM_022041.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.02
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• giant axonal neuropathy 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 16-81351535-C-G is Benign according to our data. Variant chr16-81351535-C-G is described in ClinVar as Benign. ClinVar VariationId is 261483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAN	NM_022041.4	c.168-48C>G		intron_variant	Intron 1 of 10	ENST00000648994.2	NP_071324.1
GAN	NM_001377486.1	c.-357-2870C>G		intron_variant	Intron 1 of 9		NP_001364415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAN	ENST00000648994.2	c.168-48C>G		intron_variant	Intron 1 of 10		NM_022041.4	ENSP00000497351.1

Frequencies

GnomAD3 genomes AF: 0.00601 AC: 914 AN: 152108 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0189

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0758

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.00274

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.0126 AC: 3033 AN: 240694 AF XY: 0.0114

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.0314

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0730

Gnomad FIN exome AF: 0.00299

Gnomad NFE exome AF: 0.000825

Gnomad OTH exome AF: 0.00844

GnomAD4 exome AF: 0.00912 AC: 5933 AN: 650400 Hom.: 151 Cov.: 8 AF XY: 0.00872 AC XY: 3080 AN XY: 353228

African (AFR) AF: 0.000677 AC: 12 AN: 17738

American (AMR) AF: 0.0299 AC: 1299 AN: 43512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21096

East Asian (EAS) AF: 0.0775 AC: 2772 AN: 35748

South Asian (SAS) AF: 0.0157 AC: 1094 AN: 69666

European-Finnish (FIN) AF: 0.00355 AC: 183 AN: 51520

Middle Eastern (MID) AF: 0.00174 AC: 6 AN: 3442

European-Non Finnish (NFE) AF: 0.000783 AC: 293 AN: 374110

Other (OTH) AF: 0.00816 AC: 274 AN: 33568

GnomAD4 genome AF: 0.00602 AC: 917 AN: 152226 Hom.: 24 Cov.: 32 AF XY: 0.00714 AC XY: 531 AN XY: 74416

African (AFR) AF: 0.00140 AC: 58 AN: 41540

American (AMR) AF: 0.0191 AC: 292 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0756 AC: 392 AN: 5186

South Asian (SAS) AF: 0.0189 AC: 91 AN: 4818

European-Finnish (FIN) AF: 0.00274 AC: 29 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68006

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00255 Hom.: 1

Bravo AF: 0.00710

Asia WGS AF: 0.0570 AC: 200 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Benign	0.67
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs77078389; hg19: chr16-81385140;