3-67360707-A-T

Position:

• chr3-67360707-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000493112.5(SUCLG2):​c.1245T>A​(p.Asn415Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,531,746 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (6 hom.)
• Consequence: SUCLG2 ENST00000493112.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:1
• Conservation: PhyloP100: 0.503

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076165497).
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUCLG2	NM_001177599.2	c.1245T>A	p.Asn415Lys	missense_variant	11/11		NP_001171070.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SUCLG2	ENST00000493112.5	c.1245T>A	p.Asn415Lys	missense_variant	11/11	1		ENSP00000419325

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00203

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00110 AC: 147 AN: 133416 Hom.: 1 AF XY: 0.00121 AC XY: 88 AN XY: 72684

Gnomad AFR exome AF: 0.000312

Gnomad AMR exome AF: 0.000951

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.00183

Gnomad OTH exome AF: 0.000243

GnomAD4 exome AF: 0.00219 AC: 3016 AN: 1379472 Hom.: 6 Cov.: 31 AF XY: 0.00220 AC XY: 1499 AN XY: 680542

Gnomad4 AFR exome AF: 0.000634

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.000148

Gnomad4 NFE exome AF: 0.00260

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152274 Hom.: 0 Cov.: 33 AF XY: 0.000779 AC XY: 58 AN XY: 74452

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00203

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00141 Hom.: 0

Bravo AF: 0.00120

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00389 AC: 15

ExAC AF: 0.00106 AC: 16

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 415 of the SUCLG2 protein (p.Asn415Lys). This variant is present in population databases (rs192811331, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SUCLG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1394676). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

SUCLG2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 04, 2020

This variant is classified as likely 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
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.66
DANN	Benign	0.43
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	0.48	N
REVEL	Benign	0.056
Sift	Benign	0.19	T
Sift4G	Benign	0.17	T
Vest4		0.16
MutPred		0.56		Gain of ubiquitination at N415 (P = 0.0109);
MVP		0.65
MPC		0.059
ClinPred		0.0024	T
GERP RS		0.74
gMVP		0.57

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs192811331; hg19: chr3-67411131;