rs797045221

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate

The NM_006796.3(AFG3L2):​c.2062C>T​(p.Pro688Ser) 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. P688A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

AFG3L2
NM_006796.3 missense

Scores

9
8
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

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 Pathogenic. Variant got 10 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_006796.3
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-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1327420.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.872
PP5
Variant 18-12337454-G-A is Pathogenic according to our data. Variant chr18-12337454-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 987295.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-12337454-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
AFG3L2NM_006796.3 linkuse as main transcriptc.2062C>T p.Pro688Ser missense_variant 16/17 ENST00000269143.8
LOC107985154XR_002958227.2 linkuse as main transcriptn.3291+552G>A intron_variant, non_coding_transcript_variant
AFG3L2XM_011525601.4 linkuse as main transcriptc.1861C>T p.Pro621Ser missense_variant 15/16

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
AFG3L2ENST00000269143.8 linkuse as main transcriptc.2062C>T p.Pro688Ser missense_variant 16/171 NM_006796.3 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461836
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
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:
0.0000187
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Spinocerebellar ataxia type 28 Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingClinical Genetics Laboratory, University Hospital Schleswig-HolsteinJul 26, 2021- -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.070
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.70
D
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Uncertain
0.26
D
MetaRNN
Pathogenic
0.87
D
MetaSVM
Uncertain
0.39
D
MutationAssessor
Benign
2.0
M
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-7.4
D
REVEL
Uncertain
0.61
Sift
Uncertain
0.0070
D
Sift4G
Uncertain
0.013
D
Polyphen
0.95
P
Vest4
0.80
MutPred
0.35
Gain of phosphorylation at P688 (P = 0.0587);
MVP
0.95
MPC
0.56
ClinPred
0.99
D
GERP RS
5.6
Varity_R
0.84
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

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