rs45560936

Positions:

• chr11-66850932-A-C
• chr11-66850932-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001040716.2(PC):​c.2224-9T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0477 in 1,607,666 control chromosomes in the GnomAD database, including 2,092 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.036 (152 hom., cov: 33)
  • Exomes 𝑓: 0.049 (1940 hom.)
• Consequence: PC NM_001040716.2 intron
• Scores: Splicing: ADA: 0.00008145
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.911

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]

PC (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 1 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-66850932-A-C is Benign according to our data. Variant chr11-66850932-A-C is described in ClinVar as [Benign]. Clinvar id is 138578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PC	NM_001040716.2	c.2224-9T>G		intron_variant		ENST00000393960.7	NP_001035806.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PC	ENST00000393960.7	c.2224-9T>G		intron_variant		5	NM_001040716.2	ENSP00000377532.1

Frequencies

GnomAD3 genomes AF: 0.0355 AC: 5402 AN: 152072 Hom.: 152 Cov.: 33

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0276

Gnomad ASJ AF: 0.0816

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0356

Gnomad FIN AF: 0.0311

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0531

Gnomad OTH AF: 0.0402

GnomAD3 exomes AF: 0.0407 AC: 9881 AN: 242584 Hom.: 268 AF XY: 0.0436 AC XY: 5763 AN XY: 132330

Gnomad AFR exome AF: 0.00920

Gnomad AMR exome AF: 0.0188

Gnomad ASJ exome AF: 0.0801

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0427

Gnomad FIN exome AF: 0.0369

Gnomad NFE exome AF: 0.0548

Gnomad OTH exome AF: 0.0470

GnomAD4 exome AF: 0.0490 AC: 71328 AN: 1455476 Hom.: 1940 Cov.: 33 AF XY: 0.0491 AC XY: 35592 AN XY: 724286

Gnomad4 AFR exome AF: 0.00986

Gnomad4 AMR exome AF: 0.0212

Gnomad4 ASJ exome AF: 0.0813

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0433

Gnomad4 FIN exome AF: 0.0371

Gnomad4 NFE exome AF: 0.0532

Gnomad4 OTH exome AF: 0.0476

GnomAD4 genome AF: 0.0355 AC: 5404 AN: 152190 Hom.: 152 Cov.: 33 AF XY: 0.0339 AC XY: 2521 AN XY: 74398

Gnomad4 AFR AF: 0.0108

Gnomad4 AMR AF: 0.0275

Gnomad4 ASJ AF: 0.0816

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0363

Gnomad4 FIN AF: 0.0311

Gnomad4 NFE AF: 0.0531

Gnomad4 OTH AF: 0.0398

Alfa AF: 0.0357 Hom.: 48

Bravo AF: 0.0337

Asia WGS AF: 0.0170 AC: 58 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyruvate carboxylase deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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. -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2016	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 03, 2012

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.7
DANN	Benign	0.20
BranchPoint Hunter		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000081
dbscSNV1_RF	Benign	0.032
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: rs45560936; hg19: chr11-66618403;