chr12-56282430-T-C

Variant names:

• chr12-56282430-T-C
• rs201525280
• NM_004077.3:c.578A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004077.3(CS):​c.578A>G​(p.Lys193Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K193T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CS NM_004077.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.93
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004077.3. 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
	CS	NM_004077.3	MANE Select	c.578A>G	p.Lys193Arg	missense	Exon 6 of 11	NP_004068.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CS	ENST00000351328.8	TSL:1 MANE Select	c.578A>G	p.Lys193Arg	missense	Exon 6 of 11	ENSP00000342056.3	O75390
	CS	ENST00000548567.5	TSL:1	c.380A>G	p.Lys127Arg	missense	Exon 7 of 12	ENSP00000446779.1	A0A0C4DGI3
	CS	ENST00000904225.1		c.578A>G	p.Lys193Arg	missense	Exon 6 of 11	ENSP00000574284.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.00086
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.063
Sift	Benign	0.12	T
Sift4G	Benign	0.087	T
Polyphen		0.0030	B
Vest4		0.21
MutPred		0.46		Gain of catalytic residue at I189 (P = 2e-04)
MVP		0.66
MPC		1.3
ClinPred		0.71	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.29
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.94		Position offset: 0
DS_DL_spliceai		0.22		Position offset: -10

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

Other links and lift over

dbSNP: rs201525280; hg19: chr12-56676214;