rs2229745

chr11-66850319-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001040716.2(PC):c.2619C>T(p.Asn873=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0146 in 1,614,112 control chromosomes in the GnomAD database, including 317 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (33 hom., cov: 33)
  • Exomes 𝑓: 0.015 (284 hom.)
• Consequence: PC NM_001040716.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.48

Genes affected

PC (HGNC:8636): (pyruvate carboxylase) This gene encodes pyruvate carboxylase, which requires biotin and ATP to catalyse the carboxylation of pyruvate to oxaloacetate. The active enzyme is a homotetramer arranged in a tetrahedron which is located exclusively in the mitochondrial matrix. Pyruvate carboxylase is involved in gluconeogenesis, lipogenesis, insulin secretion and synthesis of the neurotransmitter glutamate. Mutations in this gene have been associated with pyruvate carboxylase deficiency. Alternatively spliced transcript variants with different 5' UTRs, but encoding the same protein, have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 11-66850319-G-A is Benign according to our data. Variant chr11-66850319-G-A is described in ClinVar as [Benign]. Clinvar id is 21227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0117 (1779/152286) while in subpopulation NFE AF= 0.0143 (973/68012). AF 95% confidence interval is 0.0136. There are 33 homozygotes in gnomad4. There are 831 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PC	NM_001040716.2	c.2619C>T	p.Asn873=	synonymous_variant	19/23	ENST00000393960.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PC	ENST00000393960.7	c.2619C>T	p.Asn873=	synonymous_variant	19/23	5	NM_001040716.2	P1

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1780 AN: 152168 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.0999

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.0132 AC: 3320 AN: 251426 Hom.: 72 AF XY: 0.0133 AC XY: 1814 AN XY: 135916

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00838

Gnomad ASJ exome AF: 0.0934

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00611

Gnomad FIN exome AF: 0.00420

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0204

GnomAD4 exome AF: 0.0150 AC: 21863 AN: 1461826 Hom.: 284 Cov.: 32 AF XY: 0.0148 AC XY: 10771 AN XY: 727204

Gnomad4 AFR exome AF: 0.00221

Gnomad4 AMR exome AF: 0.00901

Gnomad4 ASJ exome AF: 0.0946

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00652

Gnomad4 FIN exome AF: 0.00438

Gnomad4 NFE exome AF: 0.0151

Gnomad4 OTH exome AF: 0.0193

GnomAD4 genome AF: 0.0117 AC: 1779 AN: 152286 Hom.: 33 Cov.: 33 AF XY: 0.0112 AC XY: 831 AN XY: 74468

Gnomad4 AFR AF: 0.00279

Gnomad4 AMR AF: 0.0130

Gnomad4 ASJ AF: 0.0999

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00746

Gnomad4 FIN AF: 0.00367

Gnomad4 NFE AF: 0.0143

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0180 Hom.: 61

Bravo AF: 0.0126

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyruvate carboxylase deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 24, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	13
Dann	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: -13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2229745; hg19: chr11-66617790; COSMIC: COSV58992730; COSMIC: COSV58992730;