18-12348286-T-C

Variant names:

• chr18-12348286-T-C
• rs11553521
• NM_006796.3:c.1650A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006796.3(AFG3L2):​c.1650A>G​(p.Glu550Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.774 in 1,612,264 control chromosomes in the GnomAD database, including 486,115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (44628 hom., cov: 32)
  • Exomes 𝑓: 0.78 (441487 hom.)
• Consequence: AFG3L2 NM_006796.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.278
• Publications: 23 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):

• optic atrophy 12

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen
• spinocerebellar ataxia type 28

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

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 18-12348286-T-C is Benign according to our data. Variant chr18-12348286-T-C is described in ClinVar as Benign. ClinVar VariationId is 128287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.278 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.779 is higher than 0.05.

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.1650A>G	p.Glu550Glu	synonymous	Exon 13 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.1650A>G	p.Glu550Glu	synonymous	Exon 13 of 17	ENSP00000269143.2	Q9Y4W6
	AFG3L2	ENST00000889396.1		c.1857A>G	p.Glu619Glu	synonymous	Exon 14 of 18	ENSP00000559455.1
	AFG3L2	ENST00000964861.1		c.1794A>G	p.Glu598Glu	synonymous	Exon 14 of 18	ENSP00000634920.1

Frequencies

GnomAD3 genomes AF: 0.764 AC: 116068 AN: 151996 Hom.: 44587 Cov.: 32

Gnomad AFR AF: 0.768

Gnomad AMI AF: 0.765

Gnomad AMR AF: 0.652

Gnomad ASJ AF: 0.754

Gnomad EAS AF: 0.620

Gnomad SAS AF: 0.781

Gnomad FIN AF: 0.844

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.784

Gnomad OTH AF: 0.750

GnomAD2 exomes AF: 0.741 AC: 186247 AN: 251364 AF XY: 0.748

Gnomad AFR exome AF: 0.764

Gnomad AMR exome AF: 0.568

Gnomad ASJ exome AF: 0.753

Gnomad EAS exome AF: 0.611

Gnomad FIN exome AF: 0.835

Gnomad NFE exome AF: 0.781

Gnomad OTH exome AF: 0.742

GnomAD4 exome AF: 0.776 AC: 1132511 AN: 1460150 Hom.: 441487 Cov.: 38 AF XY: 0.776 AC XY: 563587 AN XY: 726486

African (AFR) AF: 0.771 AC: 25777 AN: 33442

American (AMR) AF: 0.580 AC: 25917 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.759 AC: 19832 AN: 26112

East Asian (EAS) AF: 0.602 AC: 23888 AN: 39684

South Asian (SAS) AF: 0.785 AC: 67703 AN: 86226

European-Finnish (FIN) AF: 0.831 AC: 44393 AN: 53412

Middle Eastern (MID) AF: 0.769 AC: 4435 AN: 5764

European-Non Finnish (NFE) AF: 0.787 AC: 874269 AN: 1110450

Other (OTH) AF: 0.767 AC: 46297 AN: 60342

GnomAD4 genome AF: 0.764 AC: 116161 AN: 152114 Hom.: 44628 Cov.: 32 AF XY: 0.763 AC XY: 56773 AN XY: 74364

African (AFR) AF: 0.768 AC: 31848 AN: 41470

American (AMR) AF: 0.652 AC: 9962 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.754 AC: 2614 AN: 3468

East Asian (EAS) AF: 0.621 AC: 3208 AN: 5164

South Asian (SAS) AF: 0.781 AC: 3759 AN: 4812

European-Finnish (FIN) AF: 0.844 AC: 8944 AN: 10598

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.784 AC: 53330 AN: 68002

Other (OTH) AF: 0.751 AC: 1582 AN: 2106

Alfa AF: 0.766 Hom.: 35522

Bravo AF: 0.746

Asia WGS AF: 0.698 AC: 2426 AN: 3478

EpiCase AF: 0.770

EpiControl AF: 0.768

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Spinocerebellar ataxia type 28 (2)
-	-	1	Optic atrophy 12 (1)
-	-	1	Spastic ataxia 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.2
DANN	Benign	0.47
PhyloP100		-0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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: rs11553521; hg19: chr18-12348285; COSMIC: COSV52313289; COSMIC: COSV52313289;