chr20-57561418-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_002591.4(PCK1):​c.7C>T​(p.Pro3Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00173 in 1,610,994 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00089 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0018 ( 5 hom. )

Consequence

PCK1
NM_002591.4 missense

Scores

2
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 3.65
Variant links:
Genes affected
PCK1 (HGNC:8724): (phosphoenolpyruvate carboxykinase 1) This gene is a main control point for the regulation of gluconeogenesis. The cytosolic enzyme encoded by this gene, along with GTP, catalyzes the formation of phosphoenolpyruvate from oxaloacetate, with the release of carbon dioxide and GDP. The expression of this gene can be regulated by insulin, glucocorticoids, glucagon, cAMP, and diet. Defects in this gene are a cause of cytosolic phosphoenolpyruvate carboxykinase deficiency. A mitochondrial isozyme of the encoded protein also has been characterized. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.007808417).
BP6
Variant 20-57561418-C-T is Benign according to our data. Variant chr20-57561418-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 788182.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chr20-57561418-C-T is described in Lovd as [Likely_benign].
BS2
High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PCK1NM_002591.4 linkuse as main transcriptc.7C>T p.Pro3Ser missense_variant 2/10 ENST00000319441.6
PCK1XM_024451888.2 linkuse as main transcriptc.-208C>T 5_prime_UTR_variant 2/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PCK1ENST00000319441.6 linkuse as main transcriptc.7C>T p.Pro3Ser missense_variant 2/101 NM_002591.4 P1P35558-1
PCK1ENST00000467047.1 linkuse as main transcriptn.339C>T non_coding_transcript_exon_variant 1/21
PCK1ENST00000475833.1 linkuse as main transcriptn.148C>T non_coding_transcript_exon_variant 2/22

Frequencies

GnomAD3 genomes
AF:
0.000887
AC:
135
AN:
152196
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000217
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000659
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00170
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.00132
AC:
330
AN:
249344
Hom.:
0
AF XY:
0.00134
AC XY:
181
AN XY:
134794
show subpopulations
Gnomad AFR exome
AF:
0.000309
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000876
Gnomad NFE exome
AF:
0.00266
Gnomad OTH exome
AF:
0.000819
GnomAD4 exome
AF:
0.00182
AC:
2657
AN:
1458680
Hom.:
5
Cov.:
29
AF XY:
0.00179
AC XY:
1300
AN XY:
725466
show subpopulations
Gnomad4 AFR exome
AF:
0.000209
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00117
Gnomad4 NFE exome
AF:
0.00228
Gnomad4 OTH exome
AF:
0.000995
GnomAD4 genome
AF:
0.000886
AC:
135
AN:
152314
Hom.:
0
Cov.:
33
AF XY:
0.000752
AC XY:
56
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.000217
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000659
Gnomad4 NFE
AF:
0.00171
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.00178
Hom.:
0
Bravo
AF:
0.00102
TwinsUK
AF:
0.00270
AC:
10
ALSPAC
AF:
0.00285
AC:
11
ESP6500AA
AF:
0.000908
AC:
4
ESP6500EA
AF:
0.00186
AC:
16
ExAC
AF:
0.00171
AC:
208
Asia WGS
AF:
0.000577
AC:
3
AN:
3478
EpiCase
AF:
0.00120
EpiControl
AF:
0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Phosphoenolpyruvate carboxykinase deficiency, cytosolic Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsNov 19, 2020This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2019- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 15, 2024- -
PCK1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 09, 2023This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.066
BayesDel_addAF
Benign
-0.50
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.14
T
Eigen
Benign
-0.096
Eigen_PC
Benign
0.098
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.60
T
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.0078
T
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
1.6
L
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.42
T
PROVEAN
Benign
0.11
N
REVEL
Benign
0.12
Sift
Benign
0.075
T
Sift4G
Benign
0.10
T
Polyphen
0.0080
B
Vest4
0.26
MVP
0.42
MPC
0.095
ClinPred
0.017
T
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.069
gMVP
0.74

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

LitVar

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

Other links and lift over

dbSNP: rs147120329; hg19: chr20-56136474; API