18-12353090-C-G

Variant names:

• chr18-12353090-C-G
• rs774375813
• NM_006796.3:c.1233G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_006796.3(AFG3L2):​c.1233G>C​(p.Ala411Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A411A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: AFG3L2 NM_006796.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.30
• 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]

AFG3L2 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 28

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp
• spastic ataxia 5

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• optic atrophy 12

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP7: Synonymous conserved (PhyloP=-3.3 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFG3L2	NM_006796.3	c.1233G>C	p.Ala411Ala	synonymous_variant	Exon 10 of 17	ENST00000269143.8	NP_006787.2
AFG3L2	XM_011525601.4	c.1233G>C	p.Ala411Ala	synonymous_variant	Exon 10 of 16		XP_011523903.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFG3L2	ENST00000269143.8	c.1233G>C	p.Ala411Ala	synonymous_variant	Exon 10 of 17	1	NM_006796.3	ENSP00000269143.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.0020
DANN	Benign	0.52
PhyloP100		-3.3

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: rs774375813; hg19: chr18-12353089; COSMIC: COSV52316287; COSMIC: COSV52316287;