rs8091858

chr18-12358662-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006796.3(AFG3L2):c.1026+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0248 in 1,613,348 control chromosomes in the GnomAD database, including 588 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (61 hom., cov: 33)
  • Exomes 𝑓: 0.025 (527 hom.)
• Consequence: AFG3L2 NM_006796.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001617
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.171

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 18-12358662-C-T is Benign according to our data. Variant chr18-12358662-C-T is described in ClinVar as [Benign]. Clinvar id is 136313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-12358662-C-T is described in Lovd as [Benign]. Variant chr18-12358662-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0231 (3523/152324) while in subpopulation NFE AF= 0.0307 (2086/68020). AF 95% confidence interval is 0.0296. There are 61 homozygotes in gnomad4. There are 1792 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 61 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFG3L2	NM_006796.3	c.1026+8G>A		splice_region_variant, intron_variant		ENST00000269143.8
AFG3L2	XM_011525601.4	c.1026+8G>A		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFG3L2	ENST00000269143.8	c.1026+8G>A		splice_region_variant, intron_variant		1	NM_006796.3	P1

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 3524 AN: 152206 Hom.: 61 Cov.: 33

Gnomad AFR AF: 0.00492

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.0665

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00972

Gnomad FIN AF: 0.0501

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0307

Gnomad OTH AF: 0.0259

GnomAD3 exomes AF: 0.0245 AC: 6104 AN: 249578 Hom.: 110 AF XY: 0.0243 AC XY: 3288 AN XY: 135064

Gnomad AFR exome AF: 0.00480

Gnomad AMR exome AF: 0.0164

Gnomad ASJ exome AF: 0.0618

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00869

Gnomad FIN exome AF: 0.0500

Gnomad NFE exome AF: 0.0297

Gnomad OTH exome AF: 0.0264

GnomAD4 exome AF: 0.0250 AC: 36528 AN: 1461024 Hom.: 527 Cov.: 32 AF XY: 0.0249 AC XY: 18096 AN XY: 726770

Gnomad4 AFR exome AF: 0.00353

Gnomad4 AMR exome AF: 0.0180

Gnomad4 ASJ exome AF: 0.0618

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00822

Gnomad4 FIN exome AF: 0.0454

Gnomad4 NFE exome AF: 0.0263

Gnomad4 OTH exome AF: 0.0244

GnomAD4 genome AF: 0.0231 AC: 3523 AN: 152324 Hom.: 61 Cov.: 33 AF XY: 0.0241 AC XY: 1792 AN XY: 74490

Gnomad4 AFR AF: 0.00491

Gnomad4 AMR AF: 0.0212

Gnomad4 ASJ AF: 0.0665

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00973

Gnomad4 FIN AF: 0.0501

Gnomad4 NFE AF: 0.0307

Gnomad4 OTH AF: 0.0261

Alfa AF: 0.0273 Hom.: 36

Bravo AF: 0.0204

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2013	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 26, 2016	- -

AFG3L2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 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). -

Spinocerebellar ataxia type 28 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	2.5
Dann	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.016
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: rs8091858; hg19: chr18-12358661;