rs764254189

Positions:

• chr18-12340230-T-C
• chr18-12340230-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_006796.3(AFG3L2):​c.1951A>G​(p.Arg651Gly) variant causes a missense 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 Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AFG3L2 NM_006796.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.48

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]

LOC107985154 (HGNC:):

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-12340230-T-C is Pathogenic according to our data. Variant chr18-12340230-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374935.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFG3L2	NM_006796.3	c.1951A>G	p.Arg651Gly	missense_variant	15/17	ENST00000269143.8	NP_006787.2
LOC107985154	XR_002958227.2	n.3291+3328T>C		intron_variant, non_coding_transcript_variant
AFG3L2	XM_011525601.4	c.1780-2695A>G		intron_variant			XP_011523903.1
LOC107985154	XR_001753363.2	n.781+1650T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AFG3L2	ENST00000269143.8	c.1951A>G	p.Arg651Gly	missense_variant	15/17	1	NM_006796.3	ENSP00000269143	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Spastic ataxia 5 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Jan 01, 2016

Variant c.1951A>G(p.R651G) was found to be pathogenic by Polyphen2 and SIFT software. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	0.14
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.075	D
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.65	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		0.93	P
Vest4		0.53
MutPred		0.54		Loss of stability (P = 0.0255);
MVP		0.92
MPC		1.9
ClinPred		0.94	D
GERP RS		1.5
Varity_R		0.61
gMVP		0.80

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

Other links and lift over

dbSNP: rs764254189; hg19: chr18-12340229;