rs494198

Positions:

• chr1-55052855-C-A
• chr1-55052855-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_174936.4(PCSK9):​c.799+64C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.641 in 1,609,988 control chromosomes in the GnomAD database, including 333,635 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.61 (28677 hom., cov: 33)
  • Exomes 𝑓: 0.65 (304958 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.373

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-55052855-C-A is Benign according to our data. Variant chr1-55052855-C-A is described in ClinVar as [Benign]. Clinvar id is 265935.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-55052855-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.753 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4	c.799+64C>A		intron_variant		ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5	c.799+64C>A		intron_variant		1	NM_174936.4	P2

Frequencies

GnomAD3 genomes AF: 0.607 AC: 92182 AN: 151892 Hom.: 28665 Cov.: 33

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.645

Gnomad AMR AF: 0.707

Gnomad ASJ AF: 0.641

Gnomad EAS AF: 0.773

Gnomad SAS AF: 0.565

Gnomad FIN AF: 0.547

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.651

Gnomad OTH AF: 0.650

GnomAD4 exome AF: 0.645 AC: 940430 AN: 1457978 Hom.: 304958 AF XY: 0.643 AC XY: 465953 AN XY: 725194

Gnomad4 AFR exome AF: 0.486

Gnomad4 AMR exome AF: 0.733

Gnomad4 ASJ exome AF: 0.638

Gnomad4 EAS exome AF: 0.762

Gnomad4 SAS exome AF: 0.560

Gnomad4 FIN exome AF: 0.562

Gnomad4 NFE exome AF: 0.653

Gnomad4 OTH exome AF: 0.645

GnomAD4 genome AF: 0.607 AC: 92240 AN: 152010 Hom.: 28677 Cov.: 33 AF XY: 0.603 AC XY: 44824 AN XY: 74282

Gnomad4 AFR AF: 0.491

Gnomad4 AMR AF: 0.707

Gnomad4 ASJ AF: 0.641

Gnomad4 EAS AF: 0.773

Gnomad4 SAS AF: 0.565

Gnomad4 FIN AF: 0.547

Gnomad4 NFE AF: 0.651

Gnomad4 OTH AF: 0.652

Alfa AF: 0.613 Hom.: 3432

Bravo AF: 0.618

Asia WGS AF: 0.676 AC: 2348 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:1

Benign, 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

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.3
DANN	Benign	0.73
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

Publications

LitVar

Other links and lift over

dbSNP: rs494198; hg19: chr1-55518528;