rs45560936

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

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 Gene-Disease associations (from GenCC):

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

PC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040716.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PC	NM_001040716.2	MANE Select	c.2224-9T>G	intron	N/A	NP_001035806.1	P11498-1
PC	NM_000920.4		c.2224-9T>G	intron	N/A	NP_000911.2	P11498-1
PC	NM_001439352.1		c.2224-9T>G	intron	N/A	NP_001426281.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PC	ENST00000393960.7	TSL:5 MANE Select	c.2224-9T>G	intron	N/A	ENSP00000377532.1	P11498-1
PC	ENST00000393955.6	TSL:1	c.2224-9T>G	intron	N/A	ENSP00000377527.2	P11498-1
PC	ENST00000393958.7	TSL:1	c.2224-9T>G	intron	N/A	ENSP00000377530.2	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

GnomAD2 exomes

AF:

0.0407

AC:

9881

AN:

242584

AF XY:

0.0436

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 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

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

4264

8529

12793

17058

21322

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2186

4372

6558

8744

10930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0355

AC:

5404

AN:

152190

Hom.:

152

Cov.:

AF XY:

0.0339

AC XY:

2521

AN XY:

74398

show subpopulations

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:

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.0531

AC:

3611

AN:

67970

Other (OTH)

AF:

0.0398

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

281

563

844

1126

1407

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0357

Hom.:

Bravo

AF:

0.0337

Asia WGS

AF:

0.0170

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pyruvate carboxylase deficiency (3)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

5.7

(source)

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)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over