18-12329583-A-AC

Position:

• chr18-12329583-A-AC

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_006796.3(AFG3L2):​c.2375_2376insG​(p.Glu793Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as no classification for the single variant (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AFG3L2 NM_006796.3 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.59

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 796 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFG3L2	NM_006796.3	c.2375_2376insG	p.Glu793Ter	frameshift_variant	17/17	ENST00000269143.8
AFG3L2	XM_011525601.4	c.2174_2175insG	p.Glu726Ter	frameshift_variant	16/16
TUBB6	NM_001303525.2	c.*403dup		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFG3L2	ENST00000269143.8	c.2375_2376insG	p.Glu793Ter	frameshift_variant	17/17	1	NM_006796.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1907449398; hg19: chr18-12329582;