NM_002591.4:c.407-65A>C

Variant names:

• chr20-57562631-A-C
• rs1040566
• NM_002591.4:c.407-65A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002591.4(PCK1):​c.407-65A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,401,362 control chromosomes in the GnomAD database, including 9,549 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2404 hom., cov: 33)
  • Exomes 𝑓: 0.097 (7145 hom.)
• Consequence: PCK1 NM_002591.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.25
• Publications: 11 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 20-57562631-A-C is Benign according to our data. Variant chr20-57562631-A-C is described in ClinVar as Benign. ClinVar VariationId is 1224911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCK1	NM_002591.4	MANE Select	c.407-65A>C		intron	N/A	NP_002582.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCK1	ENST00000319441.6	TSL:1 MANE Select	c.407-65A>C		intron	N/A	ENSP00000319814.4
	PCK1	ENST00000467047.1	TSL:1	n.1552A>C		non_coding_transcript_exon	Exon 1 of 2
	PCK1	ENST00000851909.1		c.407-65A>C		intron	N/A	ENSP00000521968.1

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23035 AN: 151988 Hom.: 2398 Cov.: 33

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.0868

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.0330

Gnomad FIN AF: 0.0923

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0979

Gnomad OTH AF: 0.144

GnomAD4 exome AF: 0.0974 AC: 121662 AN: 1249256 Hom.: 7145 Cov.: 17 AF XY: 0.0949 AC XY: 59096 AN XY: 623040

African (AFR) AF: 0.303 AC: 8939 AN: 29494

American (AMR) AF: 0.0656 AC: 2672 AN: 40704

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 2717 AN: 23588

East Asian (EAS) AF: 0.0759 AC: 2869 AN: 37782

South Asian (SAS) AF: 0.0333 AC: 2587 AN: 77678

European-Finnish (FIN) AF: 0.0998 AC: 4955 AN: 49656

Middle Eastern (MID) AF: 0.0810 AC: 356 AN: 4394

European-Non Finnish (NFE) AF: 0.0973 AC: 90805 AN: 933006

Other (OTH) AF: 0.109 AC: 5762 AN: 52954

GnomAD4 genome AF: 0.152 AC: 23061 AN: 152106 Hom.: 2404 Cov.: 33 AF XY: 0.148 AC XY: 11016 AN XY: 74356

African (AFR) AF: 0.302 AC: 12529 AN: 41474

American (AMR) AF: 0.0864 AC: 1321 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 388 AN: 3470

East Asian (EAS) AF: 0.107 AC: 554 AN: 5156

South Asian (SAS) AF: 0.0328 AC: 158 AN: 4816

European-Finnish (FIN) AF: 0.0923 AC: 978 AN: 10592

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0979 AC: 6655 AN: 67994

Other (OTH) AF: 0.147 AC: 309 AN: 2108

Alfa AF: 0.112 Hom.: 2029

Bravo AF: 0.162

Asia WGS AF: 0.0780 AC: 270 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.013
DANN	Benign	0.36
PhyloP100		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs1040566; hg19: chr20-56137687;