12-56282436-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_004077.3(CS):c.572G>A(p.Arg191Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CS NM_004077.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.50

Genes affected

CS (HGNC:2422): (citrate synthase) The protein encoded by this gene is a Krebs tricarboxylic acid cycle enzyme that catalyzes the synthesis of citrate from oxaloacetate and acetyl coenzyme A. The enzyme is found in nearly all cells capable of oxidative metablism. This protein is nuclear encoded and transported into the mitochondrial matrix, where the mature form is found. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CS
• BP4: Computational evidence support a benign effect (MetaRNN=0.28517273).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CS	NM_004077.3	c.572G>A	p.Arg191Gln	missense_variant	6/11	ENST00000351328.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CS	ENST00000351328.8	c.572G>A	p.Arg191Gln	missense_variant	6/11	1	NM_004077.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000808 AC: 2 AN: 247490 Hom.: 0 AF XY: 0.00000748 AC XY: 1 AN XY: 133744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000103 AC: 15 AN: 1451268 Hom.: 0 Cov.: 31 AF XY: 0.00000693 AC XY: 5 AN XY: 721360

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000389

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000313 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2021

The c.572G>A (p.R191Q) alteration is located in exon 6 (coding exon 6) of the CS gene. This alteration results from a G to A substitution at nucleotide position 572, causing the arginine (R) at amino acid position 191 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;.;D;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	0.92	D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.87	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;.;.;.;.;.;.
Polyphen		0.22, 0.10	.;B;B;.;.;.;.;.;.
Vest4		0.17
MutPred		0.69		.;Gain of catalytic residue at I189 (P = 3e-04);.;.;.;.;.;.;.;
MVP		0.58
MPC		1.4
ClinPred		0.54	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs757811179; hg19: chr12-56676220; COSMIC: COSV60832549; COSMIC: COSV60832549;