13-48001221-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_003850.3(SUCLA2):c.49C>G(p.Arg17Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000271 in 1,608,810 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00028 ( 1 hom. )

Consequence

SUCLA2
NM_003850.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 0.263

Publications

1 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 links:

SUCLA2-AS1 (HGNC:39965): (SUCLA2 antisense RNA 1)

SUCLA2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06358954).

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000275 (401/1456502) while in subpopulation MID AF = 0.00434 (25/5756). AF 95% confidence interval is 0.00302. There are 1 homozygotes in GnomAdExome4. There are 198 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUCLA2	NM_003850.3	MANE Select	c.49C>G	p.Arg17Gly	missense	Exon 1 of 11	NP_003841.1
	SUCLA2-AS1	NR_189308.1		n.-184G>C		upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SUCLA2	ENST00000646932.1	MANE Select	c.49C>G	p.Arg17Gly	missense	Exon 1 of 11	ENSP00000494360.1
SUCLA2	ENST00000643023.1		c.49C>G	p.Arg17Gly	missense	Exon 1 of 12	ENSP00000495664.1
SUCLA2	ENST00000434484.5	TSL:5	c.20C>G	p.Ser7Trp	missense	Exon 1 of 7	ENSP00000392771.1

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000321

AC:

AN:

236526

AF XY:

0.000318

show subpopulations

Gnomad AFR exome

AF:

0.0000698

Gnomad AMR exome

AF:

0.000150

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000348

Gnomad OTH exome

AF:

0.000520

GnomAD4 exome

AF:

0.000275

AC:

401

AN:

1456502

Hom.:

Cov.:

AF XY:

0.000273

AC XY:

198

AN XY:

724282

show subpopulations

African (AFR)

AF:

0.000210

AC:

AN:

33406

American (AMR)

AF:

0.000181

AC:

AN:

44104

Ashkenazi Jewish (ASJ)

AF:

0.00312

AC:

AN:

26000

East Asian (EAS)

AF:

0.00

AC:

AN:

39468

South Asian (SAS)

AF:

0.0000234

AC:

AN:

85432

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51806

Middle Eastern (MID)

AF:

0.00434

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000230

AC:

255

AN:

1110450

Other (OTH)

AF:

0.000383

AC:

AN:

60080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000230

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41572

American (AMR)

AF:

0.000131

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.000537

Hom.:

Bravo

AF:

0.000295

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000350

AC:

ExAC

AF:

0.000232

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Jul 06, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 05, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20843780)

Jul 30, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1

Jun 20, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria

Uncertain:3Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Nov 20, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

Apr 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SUCLA2-related disorder

Benign:1

Apr 03, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.18

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.60

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.064

MetaSVM

Benign

-0.45

MutationAssessor

Benign

0.81

PhyloP100

0.26

PrimateAI

Uncertain

0.60

PROVEAN

Benign

0.080

REVEL

Uncertain

0.39

Sift

Benign

0.11

Sift4G

Uncertain

0.029

Polyphen

0.95

Vest4

0.66

MVP

0.68

MPC

0.63

ClinPred

0.053

GERP RS

2.4

PromoterAI

-0.065

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.16

gMVP

0.51

Mutation Taster

=86/14

polymorphism

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over