rs141647723
Positions:
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The NM_003850.3(SUCLA2):āc.617A>Gā(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 (ā ā ).
Frequency
Genomes: š 0.00070 ( 0 hom., cov: 32)
Exomes š: 0.0013 ( 2 hom. )
Consequence
SUCLA2
NM_003850.3 missense
NM_003850.3 missense
Scores
3
7
4
Clinical Significance
Conservation
PhyloP100: 5.86
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]
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 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SUCLA2 | NM_003850.3 | c.617A>G | p.Glu206Gly | missense_variant | 5/11 | ENST00000646932.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SUCLA2 | ENST00000646932.1 | c.617A>G | p.Glu206Gly | missense_variant | 5/11 | NM_003850.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000703 AC: 107AN: 152190Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
107
AN:
152190
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000541 AC: 136AN: 251286Hom.: 0 AF XY: 0.000567 AC XY: 77AN XY: 135832
GnomAD3 exomes
AF:
AC:
136
AN:
251286
Hom.:
AF XY:
AC XY:
77
AN XY:
135832
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00129 AC: 1885AN: 1461256Hom.: 2 Cov.: 30 AF XY: 0.00118 AC XY: 861AN XY: 726982
GnomAD4 exome
AF:
AC:
1885
AN:
1461256
Hom.:
Cov.:
30
AF XY:
AC XY:
861
AN XY:
726982
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.000703 AC: 107AN: 152308Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42AN XY: 74480
GnomAD4 genome
?
AF:
AC:
107
AN:
152308
Hom.:
Cov.:
32
AF XY:
AC XY:
42
AN XY:
74480
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
12
ALSPAC
AF:
AC:
11
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
13
ExAC
?
AF:
AC:
70
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
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 | Invitae | 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 | - - |
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. - |
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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 19, 2021 | 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 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;.;.;D;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
H;H;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
Polyphen
P;P;.;.;.;.;.;.;.
Vest4
0.78
MVP
0.86
MPC
0.69
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at