rs151344519

Variant names:

• chr18-12337494-GG-TA
• rs151344519
• NM_006796.3:c.2021_2022delCCinsTA

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PP2 PP3 PP5

The NM_006796.3(AFG3L2):​c.2021_2022delCCinsTA​(p.Ser674Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AFG3L2 NM_006796.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.56
• Publications: 5 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_006796.3
• 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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 18-12337494-GG-TA is Pathogenic according to our data. Variant chr18-12337494-GG-TA is described in ClinVar as Pathogenic. ClinVar VariationId is 5471.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFG3L2	NM_006796.3	c.2021_2022delCCinsTA	p.Ser674Leu	missense_variant		ENST00000269143.8	NP_006787.2
AFG3L2	XM_011525601.4	c.1820_1821delCCinsTA	p.Ser607Leu	missense_variant			XP_011523903.1
LOC107985154	XR_002958227.2	n.3291+592_3291+593delGGinsTA		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFG3L2	ENST00000269143.8	c.2021_2022delCCinsTA	p.Ser674Leu	missense_variant		1	NM_006796.3	ENSP00000269143.2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Spinocerebellar ataxia type 28 Pathogenic:1

Apr 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6
Mutation Taster		=8/92	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs151344519; hg19: chr18-12337493;