1-55052517-AC-A

Position:

• chr1-55052517-AC-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_174936.4(PCSK9):​c.657+114delC variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.55 (26536 hom., cov: 0)
  • Exomes 𝑓: 0.67 (333988 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.574

Genes affected

PCSK9 (HGNC:20001): (proprotein convertase subtilisin/kexin type 9) This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an autocatalytic processing event with its prosegment in the ER and is constitutively secreted as an inactive protease into the extracellular matrix and trans-Golgi network. It is expressed in liver, intestine and kidney tissues and escorts specific receptors for lysosomal degradation. It plays a role in cholesterol and fatty acid metabolism. Mutations in this gene have been associated with autosomal dominant familial hypercholesterolemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

PCSK9 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.657+114delC		intron_variant		ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.657+114delC		intron_variant		1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.554 AC: 83803 AN: 151308 Hom.: 26533 Cov.: 0

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.664

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.747

Gnomad SAS AF: 0.591

Gnomad FIN AF: 0.767

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.678

Gnomad OTH AF: 0.565

GnomAD4 exome AF: 0.675 AC: 974188 AN: 1443460 Hom.: 333988 Cov.: 0 AF XY: 0.672 AC XY: 481372 AN XY: 716754

Gnomad4 AFR exome AF: 0.202

Gnomad4 AMR exome AF: 0.705

Gnomad4 ASJ exome AF: 0.563

Gnomad4 EAS exome AF: 0.736

Gnomad4 SAS exome AF: 0.585

Gnomad4 FIN exome AF: 0.753

Gnomad4 NFE exome AF: 0.694

Gnomad4 OTH exome AF: 0.648

GnomAD4 genome AF: 0.554 AC: 83824 AN: 151426 Hom.: 26536 Cov.: 0 AF XY: 0.563 AC XY: 41653 AN XY: 74028

Gnomad4 AFR AF: 0.224

Gnomad4 AMR AF: 0.664

Gnomad4 ASJ AF: 0.571

Gnomad4 EAS AF: 0.747

Gnomad4 SAS AF: 0.592

Gnomad4 FIN AF: 0.767

Gnomad4 NFE AF: 0.678

Gnomad4 OTH AF: 0.566

Alfa AF: 0.406 Hom.: 941

Bravo AF: 0.530

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Mar 01, 2016

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Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs397735050; hg19: chr1-55518190;