rs62636645

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.110T>G(p.Leu37Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00414 in 1,614,086 control chromosomes in the GnomAD database, including 218 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 129 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 89 hom. )

Consequence

SUCLA2
NM_003850.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 6.88

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027971268).

BP6

Variant 13-47997004-A-C is Benign according to our data. Variant chr13-47997004-A-C is described in ClinVar as Benign. ClinVar VariationId is 139363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0744 is higher than 0.05.

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.110T>G	p.Leu37Trp	missense	Exon 2 of 11	NP_003841.1	E5KS60

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SUCLA2	ENST00000646932.1	MANE Select	c.110T>G	p.Leu37Trp	missense	Exon 2 of 11	ENSP00000494360.1	Q9P2R7-1
SUCLA2	ENST00000642944.1		c.-65T>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 11	ENSP00000495674.1	A0A2R8YDQ9
SUCLA2	ENST00000646804.1		c.-65T>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 11	ENSP00000493977.1	A0A2R8YDQ9

Frequencies

GnomAD3 genomes

AF:

0.0219

AC:

3338

AN:

152162

Hom.:

126

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0764

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00805

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.0138

GnomAD2 exomes

AF:

0.00569

AC:

1430

AN:

251236

AF XY:

0.00397

show subpopulations

Gnomad AFR exome

AF:

0.0750

Gnomad AMR exome

AF:

0.00390

Gnomad ASJ exome

AF:

0.00198

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00228

AC:

3327

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

1486

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.0757

AC:

2533

AN:

33474

American (AMR)

AF:

0.00400

AC:

179

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00195

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.000197

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00832

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000174

AC:

193

AN:

1111980

Other (OTH)

AF:

0.00507

AC:

306

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

163

326

490

653

816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

252

336

420

<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:

0.0221

AC:

3358

AN:

152280

Hom.:

129

Cov.:

AF XY:

0.0214

AC XY:

1595

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0766

AC:

3182

AN:

41536

American (AMR)

AF:

0.00804

AC:

123

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

68026

Other (OTH)

AF:

0.0137

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

158

316

474

632

790

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.00801

Hom.:

Bravo

AF:

0.0253

ESP6500AA

AF:

0.0760

AC:

335

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00673

AC:

817

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000652

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.69

PhyloP100

6.9

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.96

REVEL

Benign

0.16

Sift

Benign

0.16

Sift4G

Benign

0.12

Polyphen

0.95

Vest4

0.61

MVP

0.81

MPC

0.81

ClinPred

0.019

GERP RS

5.7

Varity_R

0.085

gMVP

0.53

Mutation Taster

=84/16

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over