rs141647723

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBS1BS2

The NM_003850.3(SUCLA2):c.617A>G(p.Glu206Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00123 in 1,613,564 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 2 hom. )

Consequence

SUCLA2
NM_003850.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 5.86

Publications

4 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: AR, Mitochondrial Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

SUCLA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.095501214).

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00129 (1885/1461256) while in subpopulation NFE AF = 0.00163 (1816/1111636). AF 95% confidence interval is 0.00157. There are 2 homozygotes in GnomAdExome4. There are 861 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,Mitochondrial gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003850.3. 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
	SUCLA2	NM_003850.3	MANE Select	c.617A>G	p.Glu206Gly	missense	Exon 5 of 11	NP_003841.1	E5KS60

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SUCLA2	ENST00000646932.1	MANE Select	c.617A>G	p.Glu206Gly	missense	Exon 5 of 11	ENSP00000494360.1	Q9P2R7-1
SUCLA2	ENST00000643023.1		c.617A>G	p.Glu206Gly	missense	Exon 5 of 12	ENSP00000495664.1	A0A2R8Y6Y7
SUCLA2	ENST00000853364.1		c.674A>G	p.Glu225Gly	missense	Exon 6 of 12	ENSP00000523423.1

Frequencies

GnomAD3 genomes

AF:

0.000703

AC:

107

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00113

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000541

AC:

136

AN:

251286

AF XY:

0.000567

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00103

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00129

AC:

1885

AN:

1461256

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

861

AN XY:

726982

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33470

American (AMR)

AF:

0.000246

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39648

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00163

AC:

1816

AN:

1111636

Other (OTH)

AF:

0.000729

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

177

266

354

443

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<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:

0.000703

AC:

107

AN:

152308

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000409

AC:

AN:

41572

American (AMR)

AF:

0.000589

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00113

AC:

AN:

68020

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000651

Hom.:

Bravo

AF:

0.000858

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.000576

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.00101

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (4)

not provided (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.97

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.096

MetaSVM

Uncertain

-0.079

MutationAssessor

Pathogenic

3.7

PhyloP100

5.9

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.37

Sift

Benign

0.33

Sift4G

Benign

0.33

Polyphen

0.93

Vest4

0.78

MVP

0.86

MPC

0.69

ClinPred

0.20

GERP RS

5.8

Varity_R

0.76

gMVP

0.83

Mutation Taster

=23/77

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over