rs61738833

Variant names:

• chr12-56276015-G-A
• rs61738833
• NM_004077.3:c.769C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_004077.3(CS):​c.769C>T​(p.Leu257Leu) 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.89
• Publications: 6 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: Benign. The variant received -14 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 VariationId is 777689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1359 AD gene.

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.769C>T	p.Leu257Leu	synonymous	Exon 7 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.769C>T	p.Leu257Leu	synonymous	Exon 7 of 11	ENSP00000342056.3	O75390
	CS	ENST00000548567.5	TSL:1	c.571C>T	p.Leu191Leu	synonymous	Exon 8 of 12	ENSP00000446779.1	A0A0C4DGI3
	CS	ENST00000904225.1		c.733C>T	p.Leu245Leu	synonymous	Exon 7 of 11	ENSP00000574284.1

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

GnomAD2 exomes AF: 0.00797 AC: 2003 AN: 251384 AF XY: 0.00787

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 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

African (AFR) AF: 0.00260 AC: 87 AN: 33480

American (AMR) AF: 0.00879 AC: 393 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00108 AC: 93 AN: 86258

European-Finnish (FIN) AF: 0.00768 AC: 410 AN: 53420

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5766

European-Non Finnish (NFE) AF: 0.0149 AC: 16585 AN: 1111996

Other (OTH) AF: 0.0127 AC: 770 AN: 60396

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

African (AFR) AF: 0.00291 AC: 121 AN: 41564

American (AMR) AF: 0.0126 AC: 192 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4832

European-Finnish (FIN) AF: 0.00914 AC: 97 AN: 10616

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0133 AC: 905 AN: 68026

Other (OTH) AF: 0.0133 AC: 28 AN: 2104

Alfa AF: 0.0103 Hom.: 24

Bravo AF: 0.00849

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0119

EpiControl AF: 0.0127

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.2
DANN	Benign	0.73
PhyloP100		4.9
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

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