chr12-56283855-C-G

Variant names:

• chr12-56283855-C-G
• rs561428964
• NM_004077.3:c.204G>C

Variant summary

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

The NM_004077.3(CS):​c.204G>C​(p.Met68Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: CS NM_004077.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.29

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12084523).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CS	NM_004077.3	c.204G>C	p.Met68Ile	missense_variant, splice_region_variant	Exon 4 of 11	ENST00000351328.8	NP_004068.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CS	ENST00000351328.8	c.204G>C	p.Met68Ile	missense_variant, splice_region_variant	Exon 4 of 11	1	NM_004077.3	ENSP00000342056.3

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151646 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151764 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74144

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.20	.;T;.;.;T;T;.;T;T;T;.;.;T;T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.0054
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;.;D;T;D;D;D;D;D;D;D
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	.;L;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.94	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.068
Sift	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.30	T;T;T;T;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.0	.;B;B;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.20
MutPred		0.40		.;Gain of catalytic residue at D66 (P = 0);.;Gain of catalytic residue at D66 (P = 0);.;.;.;.;.;.;.;Gain of catalytic residue at D66 (P = 0);Gain of catalytic residue at D66 (P = 0);.;.;
MVP		0.32
MPC		1.3
ClinPred		0.21	T
GERP RS		4.7
Varity_R		0.47
gMVP		0.60

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: rs561428964; hg19: chr12-56677639;