18-12337454-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_006796.3(AFG3L2):​c.2062C>G​(p.Pro688Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P688S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

AFG3L2
NM_006796.3 missense

Scores

7
11
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 9.56
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr18-12337454-G-A is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.9

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AFG3L2NM_006796.3 linkc.2062C>G p.Pro688Ala missense_variant Exon 16 of 17 ENST00000269143.8 NP_006787.2 Q9Y4W6Q8TA92
AFG3L2XM_011525601.4 linkc.1861C>G p.Pro621Ala missense_variant Exon 15 of 16 XP_011523903.1
LOC107985154XR_002958227.2 linkn.3291+552G>C intron_variant Intron 1 of 1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AFG3L2ENST00000269143.8 linkc.2062C>G p.Pro688Ala missense_variant Exon 16 of 17 1 NM_006796.3 ENSP00000269143.2 Q9Y4W6

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:2
Sep 11, 2014
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 18, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: AFG3L2 c.2062C>G (p.Pro688Ala) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251476 control chromosomes. c.2062C>G has been reported in the literature as a heterozygous genotype in at-least three comprehensively genotyped and clinically evaluated individuals affected with Spinocerebellar Ataxia Type 28 (example, Sun_2019, Coutelier_2017). The variant segregated with disease in at-least one family reporting an affected mother and brother and inheritance from the affected mother to the affected proband with cerebellar atrophy and hyperreflexia, who underwent a comprehensive NGS based work up on a panel of 441 genes implicated in pure forms of cerebellar ataxia (Sun_2019). One of these individuals also displayed a T1-weighted sagittal and axial brain MRI showing slight vermian atrophy and underwent a NGS based workup on a panel of 65 genes involved in ataxia (Coutelier_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, until additional clinical cases supported by concrete functional studies are reported, the variant was classified as VUS-possibly pathogenic. -

not provided Uncertain:2
Aug 25, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Previously reported in the heterozygous state in individuals with ataxia and/or cerebellar atrophy; however, familial segregation information was not reported (PMID: 28444220, 29915382, 35588347); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29915382, 35588347, 28444220) -

May 12, 2021
Athena Diagnostics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.84
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.10
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.72
D
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.97
D
M_CAP
Uncertain
0.25
D
MetaRNN
Pathogenic
0.90
D
MetaSVM
Uncertain
0.46
D
MutationAssessor
Uncertain
2.3
M
PrimateAI
Uncertain
0.79
T
PROVEAN
Pathogenic
-7.4
D
REVEL
Pathogenic
0.65
Sift
Uncertain
0.0060
D
Sift4G
Uncertain
0.017
D
Polyphen
0.99
D
Vest4
0.86
MutPred
0.39
Gain of helix (P = 0.062);
MVP
0.95
MPC
0.66
ClinPred
0.99
D
GERP RS
5.6
Varity_R
0.84
gMVP
0.61

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs797045221; hg19: chr18-12337453; API