rs625619

Positions:

• chr1-55052493-G-A
• chr1-55052493-G-C
• chr1-55052493-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_174936.4(PCSK9):​c.657+82G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 1,607,646 control chromosomes in the GnomAD database, including 262,931 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (21035 hom., cov: 33)
  • Exomes 𝑓: 0.57 (241896 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.169

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-55052493-G-A is Benign according to our data. Variant chr1-55052493-G-A is described in ClinVar as [Benign]. Clinvar id is 265925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55052493-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.657+82G>A		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+82G>A		intron_variant		1	NM_174936.4	ENSP00000303208	P2

Frequencies

GnomAD3 genomes AF: 0.508 AC: 76899 AN: 151350 Hom.: 21027 Cov.: 33

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.602

Gnomad AMR AF: 0.655

Gnomad ASJ AF: 0.502

Gnomad EAS AF: 0.781

Gnomad SAS AF: 0.538

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.558

GnomAD4 exome AF: 0.573 AC: 833684 AN: 1456178 Hom.: 241896 Cov.: 38 AF XY: 0.571 AC XY: 413172 AN XY: 723892

Gnomad4 AFR exome AF: 0.292

Gnomad4 AMR exome AF: 0.692

Gnomad4 ASJ exome AF: 0.495

Gnomad4 EAS exome AF: 0.763

Gnomad4 SAS exome AF: 0.525

Gnomad4 FIN exome AF: 0.481

Gnomad4 NFE exome AF: 0.580

Gnomad4 OTH exome AF: 0.567

GnomAD4 genome AF: 0.508 AC: 76941 AN: 151468 Hom.: 21035 Cov.: 33 AF XY: 0.507 AC XY: 37505 AN XY: 73954

Gnomad4 AFR AF: 0.301

Gnomad4 AMR AF: 0.655

Gnomad4 ASJ AF: 0.502

Gnomad4 EAS AF: 0.782

Gnomad4 SAS AF: 0.538

Gnomad4 FIN AF: 0.470

Gnomad4 NFE AF: 0.583

Gnomad4 OTH AF: 0.559

Alfa AF: 0.375 Hom.: 1158

Bravo AF: 0.514

Asia WGS AF: 0.630 AC: 2190 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.6
DANN	Benign	0.55

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: rs625619; hg19: chr1-55518166;