12-56300197-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_004077.3(CS):c.5C>G(p.Ala2Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000115 in 1,568,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: CS NM_004077.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.44

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]

CNPY2-AS1 (HGNC:55480): (CNPY2 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CS
• BP4: Computational evidence support a benign effect (MetaRNN=0.051139772).
• BS2: High AC in GnomAd at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CS	NM_004077.3	c.5C>G	p.Ala2Gly	missense_variant	1/11	ENST00000351328.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CS	ENST00000351328.8	c.5C>G	p.Ala2Gly	missense_variant	1/11	1	NM_004077.3	P1
CNPY2-AS1	ENST00000660360.2	n.94+10G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152250 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000246 AC: 44 AN: 178940 Hom.: 0 AF XY: 0.000238 AC XY: 23 AN XY: 96588

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00103

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000404

Gnomad FIN exome AF: 0.000121

Gnomad NFE exome AF: 0.000160

Gnomad OTH exome AF: 0.000842

GnomAD4 exome AF: 0.000119 AC: 168 AN: 1416176 Hom.: 0 Cov.: 30 AF XY: 0.000130 AC XY: 91 AN XY: 701152

Gnomad4 AFR exome AF: 0.0000314

Gnomad4 AMR exome AF: 0.000531

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.0000596

Gnomad4 NFE exome AF: 0.0000743

Gnomad4 OTH exome AF: 0.000256

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152368 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74514

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000228 Hom.: 1

Bravo AF: 0.0000945

ExAC AF: 0.000152 AC: 18

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

Mar 16, 2022

The c.5C>G (p.A2G) alteration is located in exon 1 (coding exon 1) of the CS gene. This alteration results from a C to G substitution at nucleotide position 5, causing the alanine (A) at amino acid position 2 to be replaced by a glycine (G). 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	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.;.;.;T;.;T;.
Eigen	Benign	-0.024
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.62	T;T;T;T;T;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.051	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.69	N;.;.;.;.;.;.;.
MutationTaster	Benign	0.69	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.85	N;N;N;N;N;N;N;N
REVEL	Benign	0.29
Sift	Uncertain	0.014	D;T;D;D;D;D;D;D
Sift4G	Benign	0.13	T;.;.;T;.;.;.;D
Polyphen		0.012	B;.;.;.;.;.;.;.
Vest4		0.34
MVP		0.40
MPC		0.069
ClinPred		0.10	T
GERP RS		4.7
Varity_R		0.43
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs147086028; hg19: chr12-56693981;