chr20-57561190-C-T

Variant names:

• chr20-57561190-C-T
• rs886056794
• NM_002591.4:c.-54C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002591.4(PCK1):​c.-54C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000034 in 293,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PCK1 NM_002591.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.479
• Publications: 0 publications found

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]

PCK1 Gene-Disease associations (from GenCC):

• phosphoenolpyruvate carboxykinase deficiency, cytosolic

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• phosphoenolpyruvate carboxykinase deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002591.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCK1	NM_002591.4	MANE Select	c.-54C>T		5_prime_UTR	Exon 1 of 10	NP_002582.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCK1	ENST00000319441.6	TSL:1 MANE Select	c.-54C>T		5_prime_UTR	Exon 1 of 10	ENSP00000319814.4	P35558-1
	PCK1	ENST00000467047.1	TSL:1	n.111C>T		non_coding_transcript_exon	Exon 1 of 2
	PCK1	ENST00000851909.1		c.-222C>T		5_prime_UTR	Exon 1 of 9	ENSP00000521968.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000340 AC: 1 AN: 293942 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 152192

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 9078

American (AMR) AF: 0.00 AC: 0 AN: 10892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9972

East Asian (EAS) AF: 0.00 AC: 0 AN: 20566

South Asian (SAS) AF: 0.0000364 AC: 1 AN: 27446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17686

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1344

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 179344

Other (OTH) AF: 0.00 AC: 0 AN: 17614

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Phosphoenolpyruvate carboxykinase deficiency, cytosolic (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.2
DANN	Benign	0.76
PhyloP100		0.48
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs886056794; hg19: chr20-56136246;