12-56276015-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_004077.3(CS):c.769C>T(p.Leu257=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0122 in 1,614,172 control chromosomes in the GnomAD database, including 184 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0089 (8 hom., cov: 31)
  • Exomes 𝑓: 0.013 (176 hom.)
• Consequence: CS NM_004077.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.89

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 12-56276015-G-A is Benign according to our data. Variant chr12-56276015-G-A is described in ClinVar as [Benign]. Clinvar id is 777689.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 1358 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CS	NM_004077.3	c.769C>T	p.Leu257=	synonymous_variant	7/11	ENST00000351328.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CS	ENST00000351328.8	c.769C>T	p.Leu257=	synonymous_variant	7/11	1	NM_004077.3	P1

Frequencies

GnomAD3 genomes AF: 0.00892 AC: 1358 AN: 152178 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00914

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00797 AC: 2003 AN: 251384 Hom.: 17 AF XY: 0.00787 AC XY: 1069 AN XY: 135872

Gnomad AFR exome AF: 0.00301

Gnomad AMR exome AF: 0.00775

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.00841

Gnomad NFE exome AF: 0.0126

Gnomad OTH exome AF: 0.00652

GnomAD4 exome AF: 0.0126 AC: 18367 AN: 1461876 Hom.: 176 Cov.: 31 AF XY: 0.0120 AC XY: 8762 AN XY: 727244

Gnomad4 AFR exome AF: 0.00260

Gnomad4 AMR exome AF: 0.00879

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00108

Gnomad4 FIN exome AF: 0.00768

Gnomad4 NFE exome AF: 0.0149

Gnomad4 OTH exome AF: 0.0127

GnomAD4 genome AF: 0.00892 AC: 1359 AN: 152296 Hom.: 8 Cov.: 31 AF XY: 0.00850 AC XY: 633 AN XY: 74454

Gnomad4 AFR AF: 0.00291

Gnomad4 AMR AF: 0.0126

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00914

Gnomad4 NFE AF: 0.0133

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.00982 Hom.: 6

Bravo AF: 0.00849

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0119

EpiControl AF: 0.0127

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	8.2
Dann	Benign	0.73
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1

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: rs61738833; hg19: chr12-56669799; COSMIC: COSV100673316; COSMIC: COSV100673316;