13-47973310-T-C

Position:

chr13-47973310-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

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

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome 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 gnomad4_exome. There are 861 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUCLA2	NM_003850.3 linkuse as main transcript	c.617A>G	p.Glu206Gly	missense_variant	5/11	ENST00000646932.1	NP_003841.1	Q9P2R7-1E5KS60Q9Y4T0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SUCLA2	ENST00000646932.1 linkuse as main transcript	c.617A>G	p.Glu206Gly	missense_variant	5/11		NM_003850.3	ENSP00000494360.1		Q9P2R7-1

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

GnomAD3 exomes

AF:

0.000541

AC:

136

AN:

251286

Hom.:

AF XY:

0.000567

AC XY:

AN XY:

135832

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 SAS exome

AF:

0.0000653

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

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00163

Gnomad4 OTH exome

AF:

0.000729

GnomAD4 genome

AF:

0.000703

AC:

107

AN:

152308

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00113

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00111

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

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 13, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 206 of the SUCLA2 protein (p.Glu206Gly). This variant is present in population databases (rs141647723, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SUCLA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 203956). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SUCLA2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 25, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 31, 2020	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 08, 2024	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2022

The c.617A>G (p.E206G) alteration is located in exon 5 (coding exon 5) of the SUCLA2 gene. This alteration results from a A to G substitution at nucleotide position 617, causing the glutamic acid (E) at amino acid position 206 to be replaced by a glycine (G). The p.E206G alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;D;.;.;.;D;D;.;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.97

.;D;D;.;D;D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.096

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

MetaSVM

Uncertain

-0.079

MutationAssessor

Pathogenic

3.7

H;H;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.9

.;D;.;.;.;D;D;.;.

REVEL

Uncertain

0.37

Sift

Benign

0.33

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

Sift4G

Benign

0.33

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

Polyphen

0.93

P;P;.;.;.;.;.;.;.

Vest4

0.78

MVP

0.86

MPC

0.69

ClinPred

0.20

GERP RS

5.8

Varity_R

0.76

gMVP

0.83

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over