18-12337522-C-A

Variant names:

• chr18-12337522-C-A
• rs1555670562
• NM_006796.3:c.1994G>T
• AFG3L2 p.Gly665Val

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_006796.3(AFG3L2):​c.1994G>T​(p.Gly665Val) 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. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G665R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AFG3L2 NM_006796.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.54
• Publications: 0 publications found

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]

TUBB6 Gene-Disease associations (from GenCC):

• facial palsy, congenital, with ptosis and velopharyngeal dysfunction

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

LOC107985154 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 7 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 chr18-12337523-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2014169.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 37 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 1.988 (below the threshold of 3.09). Trascript score misZ: 3.0639 (below the threshold of 3.09). GenCC associations: The gene is linked to spinocerebellar ataxia type 28, spastic ataxia 5, optic atrophy 12.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006796.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG3L2	NM_006796.3	MANE Select	c.1994G>T	p.Gly665Val	missense	Exon 16 of 17	NP_006787.2	Q9Y4W6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG3L2	ENST00000269143.8	TSL:1 MANE Select	c.1994G>T	p.Gly665Val	missense	Exon 16 of 17	ENSP00000269143.2	Q9Y4W6
	AFG3L2	ENST00000889396.1		c.2201G>T	p.Gly734Val	missense	Exon 17 of 18	ENSP00000559455.1
	AFG3L2	ENST00000964861.1		c.2138G>T	p.Gly713Val	missense	Exon 17 of 18	ENSP00000634920.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.9	H
PhyloP100		7.5
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-8.3	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.99
gMVP		0.94
Mutation Taster		=19/81	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1555670562;

hg19: chr18-12337521;