2-84423759-C-G

Variant names:

• chr2-84423759-C-G
• rs748995693
• NM_003849.4:c.1028G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003849.4(SUCLG1):​c.1028G>C​(p.Arg343Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,453,922 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SUCLG1 NM_003849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 6.66

Genes affected

SUCLG1 (HGNC:11449): (succinate-CoA ligase GDP/ADP-forming subunit alpha) This gene encodes the alpha subunit of the heterodimeric enzyme succinate coenzyme A ligase. This enzyme is targeted to the mitochondria and catalyzes the conversion of succinyl CoA and ADP or GDP to succinate and ATP or GTP. Mutations in this gene are the cause of the metabolic disorder fatal infantile lactic acidosis and mitochondrial DNA depletion. [provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUCLG1	NM_003849.4	c.1028G>C	p.Arg343Thr	missense_variant	Exon 9 of 9	ENST00000393868.7	NP_003840.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUCLG1	ENST00000393868.7	c.1028G>C	p.Arg343Thr	missense_variant	Exon 9 of 9	1	NM_003849.4	ENSP00000377446.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000833 AC: 2 AN: 240234 Hom.: 0 AF XY: 0.0000154 AC XY: 2 AN XY: 129620

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000186

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453922 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 722716

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial DNA depletion syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial DNA depletion syndrome 9 Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.2	M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.2	N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.032	D
Polyphen		0.32	B
Vest4		0.68
MutPred		0.49		Loss of MoRF binding (P = 0.0122);
MVP		0.91
MPC		0.064
ClinPred		0.85	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.69
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs748995693; hg19: chr2-84650883;