2-84423691-C-G

Variant names:

• chr2-84423691-C-G
• rs80166442
• NM_003849.4:c.*55G>C

Variant summary

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

The NM_003849.4(SUCLG1):​c.*55G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,546,504 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (24 hom., cov: 33)
  • Exomes 𝑓: 0.00088 (20 hom.)
• Consequence: SUCLG1 NM_003849.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.114
• Publications: 1 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-84423691-C-G is Benign according to our data. Variant chr2-84423691-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 337150.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 = 0.00922 (1404/152316) while in subpopulation AFR AF = 0.0326 (1354/41566). AF 95% confidence interval is 0.0311. There are 24 homozygotes in GnomAd4. There are 642 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

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.*55G>C		3_prime_UTR	Exon 9 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.*55G>C		3_prime_UTR	Exon 9 of 9	ENSP00000377446.2	P53597
	SUCLG1	ENST00000949558.1		c.*55G>C		3_prime_UTR	Exon 10 of 10	ENSP00000619617.1
	SUCLG1	ENST00000912793.1		c.*55G>C		3_prime_UTR	Exon 9 of 9	ENSP00000582852.1

Frequencies

GnomAD3 genomes AF: 0.00922 AC: 1404 AN: 152198 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.0327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

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: 0.0000735

Gnomad OTH AF: 0.00430

GnomAD4 exome AF: 0.000882 AC: 1230 AN: 1394188 Hom.: 20 Cov.: 26 AF XY: 0.000748 AC XY: 518 AN XY: 692518

African (AFR) AF: 0.0331 AC: 1069 AN: 32282

American (AMR) AF: 0.00107 AC: 43 AN: 40356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25322

East Asian (EAS) AF: 0.00 AC: 0 AN: 38904

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51240

Middle Eastern (MID) AF: 0.000353 AC: 2 AN: 5670

European-Non Finnish (NFE) AF: 0.0000207 AC: 22 AN: 1060648

Other (OTH) AF: 0.00161 AC: 93 AN: 57944

GnomAD4 genome AF: 0.00922 AC: 1404 AN: 152316 Hom.: 24 Cov.: 33 AF XY: 0.00862 AC XY: 642 AN XY: 74474

African (AFR) AF: 0.0326 AC: 1354 AN: 41566

American (AMR) AF: 0.00235 AC: 36 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68038

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00798 Hom.: 1

Bravo AF: 0.0105

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Mitochondrial DNA depletion syndrome (1)
-	-	1	Mitochondrial DNA depletion syndrome 9 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.9
DANN	Benign	0.62
PhyloP100		0.11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs80166442; hg19: chr2-84650815;