chr13-47942656-T-TC

Variant names:

• chr13-47942656-T-TC
• rs563064046
• NM_003850.3:c.*714dupG

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_003850.3(SUCLA2):​c.*714dupG variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 152,312 control chromosomes in the GnomAD database, including 12 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.011 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SUCLA2 NM_003850.3 splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0130
• 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: Mitochondrial, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0112 (1701/152312) while in subpopulation NFE AF = 0.0175 (1191/68030). AF 95% confidence interval is 0.0167. There are 12 homozygotes in GnomAd4. There are 810 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 12 Mitochondrial,AR 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.*714dupG		splice_region	Exon 11 of 11	NP_003841.1	E5KS60
	SUCLA2	NM_003850.3	MANE Select	c.*714dupG		3_prime_UTR	Exon 11 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.*714dupG		splice_region	Exon 11 of 11	ENSP00000494360.1	Q9P2R7-1
	SUCLA2	ENST00000646932.1	MANE Select	c.*714dupG		3_prime_UTR	Exon 11 of 11	ENSP00000494360.1	Q9P2R7-1
	SUCLA2	ENST00000944768.1		c.*714dupG		splice_region	Exon 11 of 11	ENSP00000614827.1

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1702 AN: 152194 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00335

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0175

Gnomad OTH AF: 0.0134

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 60 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 42

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0112 AC: 1701 AN: 152312 Hom.: 12 Cov.: 32 AF XY: 0.0109 AC XY: 810 AN XY: 74484

African (AFR) AF: 0.00334 AC: 139 AN: 41558

American (AMR) AF: 0.0100 AC: 153 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.0118 AC: 57 AN: 4828

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10618

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0175 AC: 1191 AN: 68030

Other (OTH) AF: 0.0128 AC: 27 AN: 2114

Alfa AF: 0.00443 Hom.: 0

Bravo AF: 0.0113

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Mitochondrial DNA depletion syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.013
Mutation Taster		=100/0	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: rs563064046; hg19: chr13-48516791;