18-12329537-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006796.3(AFG3L2):c.*28G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 1,603,688 control chromosomes in the GnomAD database, including 47,325 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6663 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40662 hom.)
• Consequence: AFG3L2 NM_006796.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.111

Genes affected

AFG3L2 (HGNC:315): (AFG3 like matrix AAA peptidase subunit 2) This gene encodes a protein localized in mitochondria and closely related to paraplegin. The paraplegin gene is responsible for an autosomal recessive form of hereditary spastic paraplegia. This gene is a candidate gene for other hereditary spastic paraplegias or neurodegenerative disorders. [provided by RefSeq, Jul 2008]

TUBB6 (HGNC:20776): (tubulin beta 6 class V) Predicted to enable GTP binding activity. Predicted to be a structural constituent of cytoskeleton. Predicted to be involved in microtubule cytoskeleton organization and mitotic cell cycle. Located in microtubule. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 18-12329537-C-G is Benign according to our data. Variant chr18-12329537-C-G is described in ClinVar as [Benign]. Clinvar id is 326101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-12329537-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFG3L2	NM_006796.3	c.*28G>C		3_prime_UTR_variant	17/17	ENST00000269143.8
TUBB6	NM_001303525.2	c.*354C>G		3_prime_UTR_variant	4/4
AFG3L2	XM_011525601.4	c.*28G>C		3_prime_UTR_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFG3L2	ENST00000269143.8	c.*28G>C		3_prime_UTR_variant	17/17	1	NM_006796.3	P1

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42779 AN: 151966 Hom.: 6644 Cov.: 32

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.233

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.291

GnomAD3 exomes AF: 0.267 AC: 67122 AN: 251116 Hom.: 9921 AF XY: 0.258 AC XY: 35089 AN XY: 135748

Gnomad AFR exome AF: 0.399

Gnomad AMR exome AF: 0.413

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.381

Gnomad SAS exome AF: 0.218

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.262

GnomAD4 exome AF: 0.229 AC: 332489 AN: 1451604 Hom.: 40662 Cov.: 29 AF XY: 0.228 AC XY: 165045 AN XY: 722768

Gnomad4 AFR exome AF: 0.394

Gnomad4 AMR exome AF: 0.406

Gnomad4 ASJ exome AF: 0.248

Gnomad4 EAS exome AF: 0.392

Gnomad4 SAS exome AF: 0.217

Gnomad4 FIN exome AF: 0.169

Gnomad4 NFE exome AF: 0.214

Gnomad4 OTH exome AF: 0.243

GnomAD4 genome AF: 0.282 AC: 42839 AN: 152084 Hom.: 6663 Cov.: 32 AF XY: 0.280 AC XY: 20824 AN XY: 74326

Gnomad4 AFR AF: 0.393

Gnomad4 AMR AF: 0.354

Gnomad4 ASJ AF: 0.252

Gnomad4 EAS AF: 0.371

Gnomad4 SAS AF: 0.220

Gnomad4 FIN AF: 0.155

Gnomad4 NFE AF: 0.217

Gnomad4 OTH AF: 0.289

Alfa AF: 0.246 Hom.: 947

Bravo AF: 0.304

Asia WGS AF: 0.314 AC: 1097 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spinocerebellar ataxia type 28 Benign:2

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	Genome-Nilou Lab	Jul 14, 2021	- -

Spastic ataxia 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Optic atrophy 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	1.5
Dann	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1129115; hg19: chr18-12329536; COSMIC: COSV52317679; COSMIC: COSV52317679;