rs35568795

Variant names:

• chr13-47988565-T-C
• rs35568795
• NM_003850.3:c.510A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003850.3(SUCLA2):​c.510A>G​(p.Ala170Ala) variant causes a synonymous change. The variant allele was found at a frequency of 0.00226 in 1,613,928 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (49 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (25 hom.)
• Consequence: SUCLA2 NM_003850.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.16
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria

  Inheritance: AR, Mitochondrial Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 13-47988565-T-C is Benign according to our data. Variant chr13-47988565-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0123 (1873/152340) while in subpopulation AFR AF = 0.0432 (1796/41588). AF 95% confidence interval is 0.0415. There are 49 homozygotes in GnomAd4. There are 889 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 49 AR,Mitochondrial gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003850.3. 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
	SUCLA2	NM_003850.3	MANE Select	c.510A>G	p.Ala170Ala	synonymous	Exon 4 of 11	NP_003841.1	E5KS60

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUCLA2	ENST00000646932.1	MANE Select	c.510A>G	p.Ala170Ala	synonymous	Exon 4 of 11	ENSP00000494360.1	Q9P2R7-1
	SUCLA2	ENST00000643023.1		c.510A>G	p.Ala170Ala	synonymous	Exon 4 of 12	ENSP00000495664.1	A0A2R8Y6Y7
	SUCLA2	ENST00000853364.1		c.567A>G	p.Ala189Ala	synonymous	Exon 5 of 12	ENSP00000523423.1

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1867 AN: 152222 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.0432

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00315 AC: 792 AN: 251308 AF XY: 0.00218

Gnomad AFR exome AF: 0.0429

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00122 AC: 1777 AN: 1461588 Hom.: 25 Cov.: 31 AF XY: 0.00109 AC XY: 791 AN XY: 727106

African (AFR) AF: 0.0424 AC: 1420 AN: 33468

American (AMR) AF: 0.00221 AC: 99 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5762

European-Non Finnish (NFE) AF: 0.0000666 AC: 74 AN: 1111918

Other (OTH) AF: 0.00280 AC: 169 AN: 60380

GnomAD4 genome AF: 0.0123 AC: 1873 AN: 152340 Hom.: 49 Cov.: 32 AF XY: 0.0119 AC XY: 889 AN XY: 74486

African (AFR) AF: 0.0432 AC: 1796 AN: 41588

American (AMR) AF: 0.00353 AC: 54 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68018

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00583 Hom.: 8

Bravo AF: 0.0143

Asia WGS AF: 0.00173 AC: 6 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.5
DANN	Benign	0.74
PhyloP100		4.2
Mutation Taster		=94/6	polymorphism

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: rs35568795; hg19: chr13-48562700;