Variant 12-56300197-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.44

Variant links:

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]

CS links:

ENSG00000144785 (HGNC:):

ENSG00000144785 links:

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

CNPY2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.051139772).

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CS	NM_004077.3 link	c.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 11	ENST00000351328.8	NP_004068.2	O75390A0A024RB75

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CS	ENST00000351328.8 link	c.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 11	1	NM_004077.3	ENSP00000342056.3		O75390
ENSG00000144785	ENST00000549318.5 link	c.593C>G	p.Ala198Gly	missense_variant	Exon 7 of 9	5		ENSP00000446743.1		F8W031

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

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:

AN:

178940

Hom.:

AF XY:

0.000238

AC XY:

AN XY:

96588

show subpopulations

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.:

Cov.:

AF XY:

0.000130

AC XY:

AN XY:

701152

show subpopulations

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:

AN:

152368

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74514

show subpopulations

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.:

Bravo

AF:

0.0000945

ExAC

AF:

0.000152

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 16, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

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

LIST_S2

Benign

0.62

T;T;T;T;T;T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.051

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.69

N;.;.;.;.;.;.;.

PrimateAI

Pathogenic

0.80

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over