chr2-84459230-T-C

Variant names:

• chr2-84459230-T-C
• rs796052053
• NM_003849.4:c.40A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP5

The NM_003849.4(SUCLG1):​c.40A>G​(p.Met14Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000858 in 1,398,350 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M14L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: SUCLG1 NM_003849.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 3.93
• Publications: 6 publications found

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]

SUCLG1 Gene-Disease associations (from GenCC):

• mitochondrial DNA depletion syndrome 9

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, PanelApp Australia
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-84459230-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 561158.
• PP5: Variant 2-84459230-T-C is Pathogenic according to our data. Variant chr2-84459230-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 203978.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003849.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUCLG1	NM_003849.4	MANE Select	c.40A>G	p.Met14Val	missense	Exon 1 of 9	NP_003840.2	P53597

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUCLG1	ENST00000393868.7	TSL:1 MANE Select	c.40A>G	p.Met14Val	missense	Exon 1 of 9	ENSP00000377446.2	P53597
	SUCLG1	ENST00000949558.1		c.40A>G	p.Met14Val	missense	Exon 1 of 10	ENSP00000619617.1
	SUCLG1	ENST00000912793.1		c.40A>G	p.Met14Val	missense	Exon 1 of 9	ENSP00000582852.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000130 AC: 2 AN: 153666 AF XY: 0.0000246

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000809

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000858 AC: 12 AN: 1398350 Hom.: 0 Cov.: 31 AF XY: 0.00000725 AC XY: 5 AN XY: 689700

African (AFR) AF: 0.0000317 AC: 1 AN: 31592

American (AMR) AF: 0.0000560 AC: 2 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 35730

South Asian (SAS) AF: 0.00 AC: 0 AN: 79222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00000834 AC: 9 AN: 1078814

Other (OTH) AF: 0.00 AC: 0 AN: 57982

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000461 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Mitochondrial DNA depletion syndrome 9 (2)
-	1	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.0095
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.075	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.9
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.31	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.026	D
Sift4G	Benign	0.10	T
Polyphen		0.32	B
Vest4		0.52
MutPred		0.37		Gain of sheet (P = 0.0028)
MVP		0.92
MPC		0.040
ClinPred		0.80	D
GERP RS		5.2
PromoterAI		-0.17	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.65
gMVP		0.83
Mutation Taster		=57/43	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs796052053; hg19: chr2-84686354;