rs45560936

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001040716.2(PC):c.2224-9T>G variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00008145

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.911

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.2224-9T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000393960.7	NP_001035806.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PC	ENST00000393960.7 linkuse as main transcript	c.2224-9T>G		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001040716.2	ENSP00000377532	P1	P11498-1

Frequencies

GnomAD3 genomes

AF:

0.0355

AC:

5402

AN:

152072

Hom.:

152

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0491

AC XY:

35592

AN XY:

724286

show subpopulations

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.:

AF XY:

0.0339

AC XY:

2521

AN XY:

74398

show subpopulations

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.:

Bravo

AF:

0.0337

Asia WGS

AF:

0.0170

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	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	Genome-Nilou Lab	Sep 05, 2021	- -

not provided

Benign:2

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over