3-67400793-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003848.4(SUCLG2):c.1121A>G(p.Asn374Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000295 in 1,612,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N374H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: SUCLG2 NM_003848.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.28

Genes affected

SUCLG2 (HGNC:11450): (succinate-CoA ligase GDP-forming subunit beta) This gene encodes a GTP-specific beta subunit of succinyl-CoA synthetase. Succinyl-CoA synthetase catalyzes the reversible reaction involving the formation of succinyl-CoA and succinate. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 5 and 12. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23278064).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUCLG2	NM_003848.4	c.1121A>G	p.Asn374Ser	missense_variant	10/11	ENST00000307227.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUCLG2	ENST00000307227.10	c.1121A>G	p.Asn374Ser	missense_variant	10/11	1	NM_003848.4	P1
SUCLG2	ENST00000493112.5	c.1121A>G	p.Asn374Ser	missense_variant	10/11	1
SUCLG2	ENST00000460567.5	c.395A>G	p.Asn132Ser	missense_variant	4/5	1

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000290 AC: 72 AN: 248684 Hom.: 0 AF XY: 0.000259 AC XY: 35 AN XY: 135000

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000391

Gnomad SAS exome AF: 0.000393

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000433

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000286 AC: 418 AN: 1460276 Hom.: 0 Cov.: 31 AF XY: 0.000275 AC XY: 200 AN XY: 726500

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.0000450

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000303

Gnomad4 SAS exome AF: 0.000279

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000324

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.000375 AC: 57 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.000377 AC XY: 28 AN XY: 74322

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000499 Hom.: 0

Bravo AF: 0.000200

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000314 AC: 38

EpiCase AF: 0.000327

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with SUCLG2-related conditions. This variant is present in population databases (rs201519398, gnomAD 0.05%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 374 of the SUCLG2 protein (p.Asn374Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	21
Dann	Uncertain	0.98
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.95	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.13
Sift	Benign	0.48	T;T
Sift4G	Benign	0.66	T;T
Polyphen		0.040	.;B
Vest4		0.42
MVP		0.68
MPC		0.047
ClinPred		0.060	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs201519398; hg19: chr3-67451217; COSMIC: COSV56205766;