18-12329563-C-T

Variant names:

• chr18-12329563-C-T
• rs113981080
• NM_006796.3:c.*2G>A

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.*2G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00335 in 1,613,702 control chromosomes in the GnomAD database, including 143 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (59 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (84 hom.)
• Consequence: AFG3L2 NM_006796.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.41

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=-0.57).
• BP6: Variant 18-12329563-C-T is Benign according to our data. Variant chr18-12329563-C-T is described in ClinVar as [Benign]. Clinvar id is 136316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFG3L2	NM_006796.3	c.*2G>A		3_prime_UTR_variant	Exon 17 of 17	ENST00000269143.8	NP_006787.2
TUBB6	NM_001303525.2	c.*380C>T		3_prime_UTR_variant	Exon 4 of 4		NP_001290454.1
AFG3L2	XM_011525601.4	c.*2G>A		3_prime_UTR_variant	Exon 16 of 16		XP_011523903.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFG3L2	ENST00000269143	c.*2G>A		3_prime_UTR_variant	Exon 17 of 17	1	NM_006796.3	ENSP00000269143.2

Frequencies

GnomAD3 genomes AF: 0.0174 AC: 2653 AN: 152138 Hom.: 59 Cov.: 33

Gnomad AFR AF: 0.0598

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00642

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00477 AC: 1200 AN: 251468 Hom.: 25 AF XY: 0.00363 AC XY: 493 AN XY: 135910

Gnomad AFR exome AF: 0.0609

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00694

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00188 AC: 2750 AN: 1461446 Hom.: 84 Cov.: 31 AF XY: 0.00163 AC XY: 1186 AN XY: 727000

Gnomad4 AFR exome AF: 0.0593

Gnomad4 AMR exome AF: 0.00326

Gnomad4 ASJ exome AF: 0.00769

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000101

Gnomad4 OTH exome AF: 0.00444

GnomAD4 genome AF: 0.0175 AC: 2660 AN: 152256 Hom.: 59 Cov.: 33 AF XY: 0.0172 AC XY: 1277 AN XY: 74458

Gnomad4 AFR AF: 0.0599

Gnomad4 AMR AF: 0.00641

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00833 Hom.: 15

Bravo AF: 0.0201

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 04, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 01, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Mar 15, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

AFG3L2-related disorder Benign:1

Aug 02, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Spinocerebellar ataxia type 28 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	1.1
DANN	Benign	0.71

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: rs113981080; hg19: chr18-12329562;