chr13-47973332-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003850.3(SUCLA2):c.595T>A(p.Ser199Thr) variant causes a missense change. The variant allele was found at a frequency of 0.787 in 1,612,708 control chromosomes in the GnomAD database, including 504,455 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.73 ( 41345 hom., cov: 31)

Exomes 𝑓: 0.79 ( 463110 hom. )

Consequence

SUCLA2
NM_003850.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 4.74

Publications

46 publications found

Variant links:

Genes affected

SUCLA2 (HGNC:11448): (succinate-CoA ligase ADP-forming subunit beta) Succinyl-CoA synthetase (SCS) is a mitochondrial matrix enzyme that acts as a heterodimer, being composed of an invariant alpha subunit and a substrate-specific beta subunit. The protein encoded by this gene is an ATP-specific SCS beta subunit that dimerizes with the SCS alpha subunit to form SCS-A, an essential component of the tricarboxylic acid cycle. SCS-A hydrolyzes ATP to convert succinate to succinyl-CoA. Defects in this gene are a cause of myopathic mitochondrial DNA depletion syndrome. A pseudogene of this gene has been found on chromosome 6. [provided by RefSeq, Jul 2008]

SUCLA2 Gene-Disease associations (from GenCC):

Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria
Inheritance: Mitochondrial, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

SUCLA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.3342432E-6).

BP6

Variant 13-47973332-A-T is Benign according to our data. Variant chr13-47973332-A-T is described in ClinVar as Benign. ClinVar VariationId is 139360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUCLA2	NM_003850.3 link	c.595T>A	p.Ser199Thr	missense_variant	Exon 5 of 11	ENST00000646932.1	NP_003841.1	Q9P2R7-1E5KS60Q9Y4T0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUCLA2	ENST00000646932.1 link	c.595T>A	p.Ser199Thr	missense_variant	Exon 5 of 11		NM_003850.3	ENSP00000494360.1		Q9P2R7-1

Frequencies

GnomAD3 genomes

AF:

0.730

AC:

110773

AN:

151840

Hom.:

41340

Cov.:

show subpopulations

Gnomad AFR

AF:

0.584

Gnomad AMI

AF:

0.919

Gnomad AMR

AF:

0.676

Gnomad ASJ

AF:

0.797

Gnomad EAS

AF:

0.799

Gnomad SAS

AF:

0.623

Gnomad FIN

AF:

0.796

Gnomad MID

AF:

0.750

Gnomad NFE

AF:

0.815

Gnomad OTH

AF:

0.760

GnomAD2 exomes

AF:

0.748

AC:

187942

AN:

251240

AF XY:

0.750

show subpopulations

Gnomad AFR exome

AF:

0.581

Gnomad AMR exome

AF:

0.635

Gnomad ASJ exome

AF:

0.780

Gnomad EAS exome

AF:

0.792

Gnomad FIN exome

AF:

0.793

Gnomad NFE exome

AF:

0.818

Gnomad OTH exome

AF:

0.761

GnomAD4 exome

AF:

0.793

AC:

1158709

AN:

1460752

Hom.:

463110

Cov.:

AF XY:

0.789

AC XY:

573638

AN XY:

726770

show subpopulations

African (AFR)

AF:

0.571

AC:

19092

AN:

33454

American (AMR)

AF:

0.638

AC:

28510

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.783

AC:

20448

AN:

26126

East Asian (EAS)

AF:

0.780

AC:

30917

AN:

39640

South Asian (SAS)

AF:

0.636

AC:

54854

AN:

86236

European-Finnish (FIN)

AF:

0.791

AC:

42139

AN:

53246

Middle Eastern (MID)

AF:

0.734

AC:

4226

AN:

5756

European-Non Finnish (NFE)

AF:

0.820

AC:

911235

AN:

1111220

Other (OTH)

AF:

0.783

AC:

47288

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

11409

22819

34228

45638

57047

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20800

41600

62400

83200

104000

<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:

0.729

AC:

110808

AN:

151956

Hom.:

41345

Cov.:

AF XY:

0.727

AC XY:

54044

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.583

AC:

24143

AN:

41394

American (AMR)

AF:

0.675

AC:

10301

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.797

AC:

2764

AN:

3470

East Asian (EAS)

AF:

0.798

AC:

4112

AN:

5152

South Asian (SAS)

AF:

0.623

AC:

3002

AN:

4816

European-Finnish (FIN)

AF:

0.796

AC:

8420

AN:

10578

Middle Eastern (MID)

AF:

0.745

AC:

219

AN:

294

European-Non Finnish (NFE)

AF:

0.815

AC:

55409

AN:

67980

Other (OTH)

AF:

0.760

AC:

1600

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1453

2905

4358

5810

7263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

840

1680

2520

3360

4200

<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:

0.785

Hom.:

12089

Bravo

AF:

0.715

TwinsUK

AF:

0.826

AC:

3064

ALSPAC

AF:

0.841

AC:

3242

ESP6500AA

AF:

0.594

AC:

2616

ESP6500EA

AF:

0.818

AC:

7035

ExAC

AF:

0.751

AC:

91230

Asia WGS

AF:

0.689

AC:

2392

AN:

3476

EpiCase

AF:

0.809

EpiControl

AF:

0.806

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jun 30, 2011

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 19, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria

Benign:3

Jan 13, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 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

AlphaMissense

Benign

0.047

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.15

DEOGEN2

Benign

0.19

T;T;.;.;.;T;T;.;.

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.47

.;T;T;.;T;T;T;T;T

MetaRNN

Benign

0.0000013

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.1

N;N;.;.;.;.;.;.;.

PhyloP100

4.7

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.030

.;N;.;.;.;N;N;.;.

REVEL

Benign

0.10

Sift

Benign

0.49

.;T;.;.;.;T;T;.;.

Sift4G

Benign

0.62

.;T;.;.;.;T;.;.;.

Polyphen

0.0

B;B;.;.;.;.;.;.;.

Vest4

0.018

MPC

0.26

ClinPred

0.012

GERP RS

4.6

Varity_R

0.070

gMVP

0.49

Mutation Taster

=98/2

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