18-12337454-G-C

Variant names:

• chr18-12337454-G-C
• rs797045221
• NM_006796.3:c.2062C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The ENST00000269143.8(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. P688T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AFG3L2 ENST00000269143.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 9.56
• Publications: 2 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: Likely_pathogenic. The variant received 9 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 ENST00000269143.8
• 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 VariationId is 1327420.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 spastic ataxia 5, optic atrophy 12, spinocerebellar ataxia type 28.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000269143.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG3L2	NM_006796.3	MANE Select	c.2062C>G	p.Pro688Ala	missense	Exon 16 of 17	NP_006787.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG3L2	ENST00000269143.8	TSL:1 MANE Select	c.2062C>G	p.Pro688Ala	missense	Exon 16 of 17	ENSP00000269143.2
	AFG3L2	ENST00000691179.1		c.1987C>G	p.Pro663Ala	missense	Exon 15 of 16	ENSP00000509010.1
	AFG3L2	ENST00000688199.1		c.1924C>G	p.Pro642Ala	missense	Exon 15 of 16	ENSP00000510237.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	2	-	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		9.6
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
Mutation Taster		=34/66	disease causing

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

Other links and lift over

dbSNP: rs797045221; hg19: chr18-12337453;