rs8097342

Positions:

• chr18-12359921-G-A
• chr18-12359921-G-C

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.752+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.756 in 1,611,922 control chromosomes in the GnomAD database, including 465,812 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (36461 hom., cov: 31)
  • Exomes 𝑓: 0.76 (429351 hom.)
• Consequence: AFG3L2 NM_006796.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00002846
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.246

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=-0.91).
• BP6: Variant 18-12359921-G-A is Benign according to our data. Variant chr18-12359921-G-A is described in ClinVar as [Benign]. Clinvar id is 136312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-12359921-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFG3L2	NM_006796.3	c.752+6C>T		splice_donor_region_variant, intron_variant		ENST00000269143.8
AFG3L2	XM_011525601.4	c.752+6C>T		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFG3L2	ENST00000269143.8	c.752+6C>T		splice_donor_region_variant, intron_variant		1	NM_006796.3	P1

Frequencies

GnomAD3 genomes AF: 0.681 AC: 103331 AN: 151832 Hom.: 36443 Cov.: 31

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.713

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.745

Gnomad EAS AF: 0.614

Gnomad SAS AF: 0.768

Gnomad FIN AF: 0.817

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.780

Gnomad OTH AF: 0.681

GnomAD3 exomes AF: 0.714 AC: 179613 AN: 251392 Hom.: 65553 AF XY: 0.726 AC XY: 98628 AN XY: 135872

Gnomad AFR exome AF: 0.482

Gnomad AMR exome AF: 0.556

Gnomad ASJ exome AF: 0.743

Gnomad EAS exome AF: 0.606

Gnomad SAS exome AF: 0.771

Gnomad FIN exome AF: 0.810

Gnomad NFE exome AF: 0.777

Gnomad OTH exome AF: 0.725

GnomAD4 exome AF: 0.764 AC: 1114860 AN: 1459972 Hom.: 429351 Cov.: 49 AF XY: 0.765 AC XY: 555322 AN XY: 726352

Gnomad4 AFR exome AF: 0.492

Gnomad4 AMR exome AF: 0.565

Gnomad4 ASJ exome AF: 0.749

Gnomad4 EAS exome AF: 0.592

Gnomad4 SAS exome AF: 0.772

Gnomad4 FIN exome AF: 0.808

Gnomad4 NFE exome AF: 0.785

Gnomad4 OTH exome AF: 0.746

GnomAD4 genome AF: 0.680 AC: 103374 AN: 151950 Hom.: 36461 Cov.: 31 AF XY: 0.682 AC XY: 50655 AN XY: 74272

Gnomad4 AFR AF: 0.495

Gnomad4 AMR AF: 0.623

Gnomad4 ASJ AF: 0.745

Gnomad4 EAS AF: 0.615

Gnomad4 SAS AF: 0.768

Gnomad4 FIN AF: 0.817

Gnomad4 NFE AF: 0.780

Gnomad4 OTH AF: 0.683

Alfa AF: 0.732 Hom.: 18251

Bravo AF: 0.654

Asia WGS AF: 0.655 AC: 2274 AN: 3478

EpiCase AF: 0.766

EpiControl AF: 0.763

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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	Sep 09, 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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 21, 2015	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 11, 2016	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Spinocerebellar ataxia type 28 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	7.8
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.0
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: rs8097342; hg19: chr18-12359920; COSMIC: COSV52313339;