18-12348286-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.278

Publications

23 publications found

Variant links:

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

AFG3L2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFG3L2	NM_006796.3 link	c.1650A>G	p.Glu550Glu	synonymous_variant	Exon 13 of 17	ENST00000269143.8	NP_006787.2
AFG3L2	XM_011525601.4 link	c.1650A>G	p.Glu550Glu	synonymous_variant	Exon 13 of 16		XP_011523903.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFG3L2	ENST00000269143.8 link	c.1650A>G	p.Glu550Glu	synonymous_variant	Exon 13 of 17	1	NM_006796.3	ENSP00000269143.2

Frequencies

GnomAD3 genomes

AF:

0.764

AC:

116068

AN:

151996

Hom.:

44587

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.776

AC XY:

563587

AN XY:

726486

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

12482

24965

37447

49930

62412

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20578

41156

61734

82312

102890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.764

AC:

116161

AN:

152114

Hom.:

44628

Cov.:

AF XY:

0.763

AC XY:

56773

AN XY:

74364

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1416

2832

4248

5664

7080

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

858

1716

2574

3432

4290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Sep 09, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 11, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Spinocerebellar ataxia type 28

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spastic ataxia 5

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Optic atrophy 12

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

4.2

(source)

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)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over