rs142289138
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_003850.3(SUCLA2):c.236C>T(p.Ser79Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000981 in 1,613,754 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00060 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0010 ( 3 hom. )
Consequence
SUCLA2
NM_003850.3 missense
NM_003850.3 missense
Scores
1
6
7
Clinical Significance
Conservation
PhyloP100: 9.44
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.018734992).
BP6
?
Variant 13-47996878-G-A is Benign according to our data. Variant chr13-47996878-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203960.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3}.
BS2
?
High Homozygotes in GnomAdExome4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SUCLA2 | NM_003850.3 | c.236C>T | p.Ser79Leu | missense_variant | 2/11 | ENST00000646932.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SUCLA2 | ENST00000646932.1 | c.236C>T | p.Ser79Leu | missense_variant | 2/11 | NM_003850.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000598 AC: 91AN: 152078Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000749 AC: 188AN: 251152Hom.: 0 AF XY: 0.000751 AC XY: 102AN XY: 135730
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GnomAD4 exome AF: 0.00102 AC: 1492AN: 1461558Hom.: 3 Cov.: 31 AF XY: 0.00103 AC XY: 751AN XY: 727088
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GnomAD4 genome ? AF: 0.000598 AC: 91AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.000699 AC XY: 52AN XY: 74408
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria Uncertain:1Benign:1
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. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | - - |
Global developmental delay Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Claritas Genomics | Feb 21, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 16, 2022 | 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 - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 01, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
SUCLA2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 07, 2023 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;.;.;.;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Benign
T
Polyphen
B;B;.;.;.;.;.;.
Vest4
0.48, 0.51
MVP
0.77
MPC
0.26
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at