rs2608555

Variant names:

• chr16-81365030-C-T
• rs2608555
• NM_022041.4:c.1293C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-81365030-C-T
• chr16-81365030-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022041.4(GAN):​c.1293C>T​(p.Tyr431Tyr) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.193
• Publications: 19 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 129131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022041.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAN	NM_022041.4	MANE Select	c.1293C>T	p.Tyr431Tyr	synonymous	Exon 8 of 11	NP_071324.1	A0A0S2Z4W2
	GAN	NM_001377486.1		c.654C>T	p.Tyr218Tyr	synonymous	Exon 7 of 10	NP_001364415.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAN	ENST00000648994.2	MANE Select	c.1293C>T	p.Tyr431Tyr	synonymous	Exon 8 of 11	ENSP00000497351.1	Q9H2C0
	GAN	ENST00000718305.1		c.1293C>T	p.Tyr431Tyr	synonymous	Exon 8 of 11	ENSP00000520738.1	Q9H2C0
	GAN	ENST00000880995.1		c.942C>T	p.Tyr314Tyr	synonymous	Exon 7 of 10	ENSP00000551054.1

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32041 AN: 151902 Hom.: 3606 Cov.: 31

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

GnomAD2 exomes AF: 0.194 AC: 48729 AN: 251396 AF XY: 0.197

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 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.: 33 AF XY: 0.226 AC XY: 163925 AN XY: 726616

African (AFR) AF: 0.185 AC: 6181 AN: 33452

American (AMR) AF: 0.128 AC: 5746 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 5276 AN: 26134

East Asian (EAS) AF: 0.0417 AC: 1655 AN: 39696

South Asian (SAS) AF: 0.149 AC: 12846 AN: 86234

European-Finnish (FIN) AF: 0.215 AC: 11507 AN: 53410

Middle Eastern (MID) AF: 0.194 AC: 1115 AN: 5756

European-Non Finnish (NFE) AF: 0.247 AC: 274066 AN: 1110820

Other (OTH) AF: 0.211 AC: 12742 AN: 60358

GnomAD4 genome AF: 0.211 AC: 32058 AN: 152020 Hom.: 3607 Cov.: 31 AF XY: 0.206 AC XY: 15293 AN XY: 74300

African (AFR) AF: 0.189 AC: 7817 AN: 41464

American (AMR) AF: 0.171 AC: 2618 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 706 AN: 3470

East Asian (EAS) AF: 0.0349 AC: 180 AN: 5164

South Asian (SAS) AF: 0.147 AC: 708 AN: 4818

European-Finnish (FIN) AF: 0.212 AC: 2241 AN: 10550

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.252 AC: 17095 AN: 67964

Other (OTH) AF: 0.221 AC: 465 AN: 2102

Alfa AF: 0.235 Hom.: 7817

Bravo AF: 0.203

Asia WGS AF: 0.111 AC: 389 AN: 3478

EpiCase AF: 0.253

EpiControl AF: 0.258

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Giant axonal neuropathy 1 (4)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.98
DANN	Benign	0.25
PhyloP100		0.19
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2608555; hg19: chr16-81398635; COSMIC: COSV73720899; COSMIC: COSV73720899;