chr18-12337454-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_ModeratePP5_Moderate

The NM_006796.3(AFG3L2):c.2062C>A(p.Pro688Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). 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)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

AFG3L2
NM_006796.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1O:1

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]

AFG3L2 links:

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]

TUBB6 links:

LOC107985154 (HGNC:):

LOC107985154 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 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, 0.908

PP5

Variant 18-12337454-G-T is Pathogenic according to our data. Variant chr18-12337454-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1327420.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFG3L2	NM_006796.3 link	c.2062C>A	p.Pro688Thr	missense_variant	Exon 16 of 17	ENST00000269143.8	NP_006787.2	Q9Y4W6Q8TA92
AFG3L2	XM_011525601.4 link	c.1861C>A	p.Pro621Thr	missense_variant	Exon 15 of 16		XP_011523903.1
LOC107985154	XR_002958227.2 link	n.3291+552G>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFG3L2	ENST00000269143.8 link	c.2062C>A	p.Pro688Thr	missense_variant	Exon 16 of 17	1	NM_006796.3	ENSP00000269143.2		Q9Y4W6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spinocerebellar ataxia type 28

Pathogenic:1Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 01, 2021

General Neurology and Ataxia Unit, Universidade Federal de Sao Paulo - Escola Paulista de Medicina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_006796.3(AFG3L2):c.2062C>A;p.(Pro688Thr) is a missense variant located within the peptidase-M41 domain of the protein, a common site of missense variants that cause autosomal dominant spinocerebellar ataxia (PMID: 20725928). This variant is absent from population databases (gnomAD, ABraOM). Previously, variants in the same amino acid where reported as disease-causing (p.P688A - PMID: 28444220; p.P688S - ClinVar Variation ID: 987295). In silico prediction tools agree on disease-causing effect of the protein (REVEL, MetaLR, MetaSVM, MetaRNN). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.48

MutationAssessor

Uncertain

2.2

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-7.4

REVEL

Uncertain

0.63

Sift

Uncertain

0.014

Sift4G

Uncertain

0.0030

Polyphen

0.99

Vest4

0.92

MutPred

0.35

Gain of phosphorylation at P688 (P = 0.0458);

MVP

0.96

MPC

0.66

ClinPred

0.99

GERP RS

5.6

Varity_R

0.87

gMVP

0.66

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over