rs45560936

Variant names:

• chr11-66850932-A-C
• rs45560936
• NM_001040716.2:c.2224-9T>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• pyruvate carboxylase deficiency disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P
• pyruvate carboxylase deficiency, benign type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• pyruvate carboxylase deficiency, infantile form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• pyruvate carboxylase deficiency, severe neonatal type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. 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 VariationId 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 rank	MANE	Protein	UniProt
PC	NM_001040716.2	c.2224-9T>G		intron_variant	Intron 17 of 22	ENST00000393960.7	NP_001035806.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PC	ENST00000393960.7	c.2224-9T>G		intron_variant	Intron 17 of 22	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

GnomAD2 exomes AF: 0.0407 AC: 9881 AN: 242584 AF XY: 0.0436

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 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

African (AFR) AF: 0.00986 AC: 330 AN: 33474

American (AMR) AF: 0.0212 AC: 949 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0813 AC: 2124 AN: 26134

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39696

South Asian (SAS) AF: 0.0433 AC: 3733 AN: 86246

European-Finnish (FIN) AF: 0.0371 AC: 1752 AN: 47250

Middle Eastern (MID) AF: 0.0794 AC: 457 AN: 5756

European-Non Finnish (NFE) AF: 0.0532 AC: 59108 AN: 1111866

Other (OTH) AF: 0.0476 AC: 2871 AN: 60342

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

African (AFR) AF: 0.0108 AC: 449 AN: 41534

American (AMR) AF: 0.0275 AC: 421 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0816 AC: 283 AN: 3468

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5174

South Asian (SAS) AF: 0.0363 AC: 175 AN: 4824

European-Finnish (FIN) AF: 0.0311 AC: 330 AN: 10608

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0531 AC: 3611 AN: 67970

Other (OTH) AF: 0.0398 AC: 84 AN: 2112

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

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 19, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

May 03, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.91
BranchPoint Hunter		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs45560936; hg19: chr11-66618403;