Genetic Variant PC:c.1513+9C>A (chr11-66853230-G-T) – ACMG Classification: Benign (-20 pts)

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.1513+9C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00443 in 1,613,358 control chromosomes in the GnomAD database, including 291 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 160 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 131 hom. )

Consequence

PC
NM_001040716.2 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.470

Publications

0 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

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 11-66853230-G-T is Benign according to our data. Variant chr11-66853230-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0831 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.1513+9C>A	intron	N/A	NP_001035806.1	P11498-1
PC	NM_000920.4		c.1513+9C>A	intron	N/A	NP_000911.2	P11498-1
PC	NM_001439352.1		c.1513+9C>A	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.1513+9C>A	intron	N/A	ENSP00000377532.1	P11498-1
PC	ENST00000393955.6	TSL:1	c.1513+9C>A	intron	N/A	ENSP00000377527.2	P11498-1
PC	ENST00000393958.7	TSL:1	c.1513+9C>A	intron	N/A	ENSP00000377530.2	P11498-1

Frequencies

GnomAD3 genomes

AF:

0.0247

AC:

3753

AN:

152002

Hom.:

160

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0856

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00982

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.0216

GnomAD2 exomes

AF:

0.00623

AC:

1564

AN:

250898

AF XY:

0.00437

show subpopulations

Gnomad AFR exome

AF:

0.0856

Gnomad AMR exome

AF:

0.00385

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000168

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00232

AC:

3392

AN:

1461238

Hom.:

131

Cov.:

AF XY:

0.00193

AC XY:

1402

AN XY:

726826

show subpopulations

African (AFR)

AF:

0.0827

AC:

2769

AN:

33470

American (AMR)

AF:

0.00459

AC:

205

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.000378

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53298

Middle Eastern (MID)

AF:

0.000706

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.0000918

AC:

102

AN:

1111700

Other (OTH)

AF:

0.00479

AC:

289

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

183

366

550

733

916

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<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:

0.0247

AC:

3755

AN:

152120

Hom.:

160

Cov.:

AF XY:

0.0232

AC XY:

1722

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0854

AC:

3544

AN:

41480

American (AMR)

AF:

0.00981

AC:

150

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

67982

Other (OTH)

AF:

0.0214

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

160

320

481

641

801

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.00634

Hom.:

Bravo

AF:

0.0282

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pyruvate carboxylase deficiency (3)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.90

(source)

DANN

Benign

0.80

PhyloP100

-0.47

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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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