Genetic Variant NM_001040716.2:c.-1+20279C>G (chr11-66932151-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001040716.2(PC):c.-1+20279C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 152,066 control chromosomes in the GnomAD database, including 6,868 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.29 ( 6868 hom., cov: 31)

Consequence

PC
NM_001040716.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.53

Publications

3 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: 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

PC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PC	NM_001040716.2 link	c.-1+20279C>G		intron_variant	Intron 3 of 22	ENST00000393960.7	NP_001035806.1	P11498-1A0A024R5C5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PC	ENST00000393960.7 link	c.-1+20279C>G		intron_variant	Intron 3 of 22	5	NM_001040716.2	ENSP00000377532.1		P11498-1

Frequencies

GnomAD3 genomes

AF:

0.295

AC:

44782

AN:

151948

Hom.:

6859

Cov.:

show subpopulations

Gnomad AFR

AF:

0.230

Gnomad AMI

AF:

0.333

Gnomad AMR

AF:

0.237

Gnomad ASJ

AF:

0.348

Gnomad EAS

AF:

0.253

Gnomad SAS

AF:

0.186

Gnomad FIN

AF:

0.340

Gnomad MID

AF:

0.358

Gnomad NFE

AF:

0.348

Gnomad OTH

AF:

0.295

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.295

AC:

44820

AN:

152066

Hom.:

6868

Cov.:

AF XY:

0.292

AC XY:

21684

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.230

AC:

9548

AN:

41490

American (AMR)

AF:

0.237

AC:

3611

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.348

AC:

1209

AN:

3470

East Asian (EAS)

AF:

0.252

AC:

1306

AN:

5176

South Asian (SAS)

AF:

0.186

AC:

894

AN:

4812

European-Finnish (FIN)

AF:

0.340

AC:

3597

AN:

10570

Middle Eastern (MID)

AF:

0.364

AC:

107

AN:

294

European-Non Finnish (NFE)

AF:

0.347

AC:

23620

AN:

67972

Other (OTH)

AF:

0.296

AC:

625

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1575

3150

4724

6299

7874

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

452

904

1356

1808

2260

<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:

0.206

Hom.:

489

Bravo

AF:

0.288

Asia WGS

AF:

0.226

AC:

788

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.6

(source)

DANN

Benign

0.64

PhyloP100

1.5

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over