3-67375857-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003848.4(SUCLG2):c.1186A>G(p.Thr396Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.104 in 1,612,796 control chromosomes in the GnomAD database, including 9,536 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.088 (693 hom., cov: 33)
  • Exomes 𝑓: 0.11 (8843 hom.)
• Consequence: SUCLG2 NM_003848.4 missense, splice_region
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.19

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044909418).
• BP6: Variant 3-67375857-T-C is Benign according to our data. Variant chr3-67375857-T-C is described in ClinVar as [Benign]. Clinvar id is 3056708.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUCLG2	NM_003848.4	c.1186A>G	p.Thr396Ala	missense_variant, splice_region_variant	11/11	ENST00000307227.10
SUCLG2	XM_047449140.1	c.1042A>G	p.Thr348Ala	missense_variant, splice_region_variant	11/11
SUCLG2	XM_017007420.3	c.*605A>G		3_prime_UTR_variant	11/11
SUCLG2	NM_001177599.2	c.1184-15089A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUCLG2	ENST00000307227.10	c.1186A>G	p.Thr396Ala	missense_variant, splice_region_variant	11/11	1	NM_003848.4	P1
SUCLG2	ENST00000460567.5	c.460A>G	p.Thr154Ala	missense_variant, splice_region_variant	5/5	1
SUCLG2	ENST00000493112.5	c.1184-15089A>G		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.0878 AC: 13355 AN: 152154 Hom.: 696 Cov.: 33

Gnomad AFR AF: 0.0475

Gnomad AMI AF: 0.0440

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.0416

Gnomad SAS AF: 0.0539

Gnomad FIN AF: 0.0400

Gnomad MID AF: 0.242

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.129

GnomAD3 exomes AF: 0.0904 AC: 22369 AN: 247422 Hom.: 1254 AF XY: 0.0925 AC XY: 12398 AN XY: 134082

Gnomad AFR exome AF: 0.0455

Gnomad AMR exome AF: 0.0697

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.0371

Gnomad SAS exome AF: 0.0567

Gnomad FIN exome AF: 0.0411

Gnomad NFE exome AF: 0.120

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.105 AC: 153683 AN: 1460524 Hom.: 8843 Cov.: 40 AF XY: 0.105 AC XY: 76475 AN XY: 726394

Gnomad4 AFR exome AF: 0.0457

Gnomad4 AMR exome AF: 0.0703

Gnomad4 ASJ exome AF: 0.179

Gnomad4 EAS exome AF: 0.0340

Gnomad4 SAS exome AF: 0.0575

Gnomad4 FIN exome AF: 0.0427

Gnomad4 NFE exome AF: 0.116

Gnomad4 OTH exome AF: 0.105

GnomAD4 genome AF: 0.0876 AC: 13339 AN: 152272 Hom.: 693 Cov.: 33 AF XY: 0.0838 AC XY: 6238 AN XY: 74460

Gnomad4 AFR AF: 0.0474

Gnomad4 AMR AF: 0.107

Gnomad4 ASJ AF: 0.175

Gnomad4 EAS AF: 0.0419

Gnomad4 SAS AF: 0.0541

Gnomad4 FIN AF: 0.0400

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.126

Alfa AF: 0.116 Hom.: 1712

Bravo AF: 0.0918

TwinsUK AF: 0.120 AC: 444

ALSPAC AF: 0.125 AC: 480

ESP6500AA AF: 0.0489 AC: 189

ESP6500EA AF: 0.120 AC: 995

ExAC AF: 0.0892 AC: 10779

Asia WGS AF: 0.0460 AC: 161 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SUCLG2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	25
Dann	Uncertain	0.98
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	2.3e-8	P;P
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.64	P
Vest4		0.28
ClinPred		0.096	T
GERP RS		5.4
Varity_R		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs35494829; hg19: chr3-67426281; COSMIC: COSV56206071;