rs748620956

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001040716.2(PC):​c.1185+5_1185+8del variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000336 in 1,605,122 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00034 ( 1 hom. )

Consequence

PC
NM_001040716.2 splice_donor_5th_base, intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 1.25
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PCNM_001040716.2 linkuse as main transcriptc.1185+5_1185+8del splice_donor_5th_base_variant, intron_variant ENST00000393960.7 NP_001035806.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PCENST00000393960.7 linkuse as main transcriptc.1185+5_1185+8del splice_donor_5th_base_variant, intron_variant 5 NM_001040716.2 ENSP00000377532 P1P11498-1

Frequencies

GnomAD3 genomes
AF:
0.000263
AC:
40
AN:
151892
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000486
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000259
AC:
63
AN:
243580
Hom.:
0
AF XY:
0.000279
AC XY:
37
AN XY:
132488
show subpopulations
Gnomad AFR exome
AF:
0.000189
Gnomad AMR exome
AF:
0.000203
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000427
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000337
Gnomad OTH exome
AF:
0.000498
GnomAD4 exome
AF:
0.000343
AC:
499
AN:
1453230
Hom.:
1
AF XY:
0.000349
AC XY:
252
AN XY:
722878
show subpopulations
Gnomad4 AFR exome
AF:
0.0000898
Gnomad4 AMR exome
AF:
0.000202
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000430
Gnomad4 FIN exome
AF:
0.0000209
Gnomad4 NFE exome
AF:
0.000392
Gnomad4 OTH exome
AF:
0.000200
GnomAD4 genome
AF:
0.000263
AC:
40
AN:
151892
Hom.:
0
Cov.:
32
AF XY:
0.000283
AC XY:
21
AN XY:
74184
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000486
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000217
Hom.:
0
Bravo
AF:
0.000208
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000654
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Pyruvate carboxylase deficiency Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 08, 2022This sequence change falls in intron 10 of the PC gene. It does not directly change the encoded amino acid sequence of the PC protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs748620956, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with PC-related conditions. ClinVar contains an entry for this variant (Variation ID: 426656). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria providedclinical testingCounsylSep 05, 2017- -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsJun 02, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 30, 2024Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 08, 2024Variant summary: PC c.1185+5_1185+8delGCGG removes 4 nucleotides located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: three predict the variant abolishes a 5' splicing donor site, while one predicts the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00034 in 1,605,122 control chromosomes in the gnomAD database (v4.0 dataset), including 1 homozygote. This frequency is not higher than the estimated maximum expected for a pathogenic variant in PC causing Pyruvate Carboxylase Deficiency (0.00034 vs 0.0022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1185+5_1185+8delGCGG in individuals affected with Pyruvate Carboxylase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 426656). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 28, 2021The c.1185+5_1185+8delGCGG alteration is located in Intron 10 (E) of the PC gene. This alteration consists of a deletion of 4 nucleotides between nucleotide positions c.11855 and c.11858 Intron 10 (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.66
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.66
Position offset: -38
DS_DL_spliceai
0.22
Position offset: 9

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.

Other links and lift over

dbSNP: rs748620956; hg19: chr11-66633649; API