rs494198

Variant names:

• chr1-55052855-C-A
• rs494198
• NM_174936.4:c.799+64C>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.373
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, autosomal dominant, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• homozygous familial hypercholesterolemia

  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=-0.87).
• BP6: Variant 1-55052855-C-A is Benign according to our data. Variant chr1-55052855-C-A is described in ClinVar as Benign. ClinVar VariationId is 265935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.799+64C>A		intron_variant	Intron 5 of 11	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.799+64C>A		intron_variant	Intron 5 of 11	1	NM_174936.4	ENSP00000303208.5

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

African (AFR) AF: 0.486 AC: 16220 AN: 33386

American (AMR) AF: 0.733 AC: 32572 AN: 44430

Ashkenazi Jewish (ASJ) AF: 0.638 AC: 16662 AN: 26096

East Asian (EAS) AF: 0.762 AC: 30190 AN: 39602

South Asian (SAS) AF: 0.560 AC: 48161 AN: 86034

European-Finnish (FIN) AF: 0.562 AC: 29263 AN: 52026

Middle Eastern (MID) AF: 0.653 AC: 3631 AN: 5564

European-Non Finnish (NFE) AF: 0.653 AC: 724896 AN: 1110586

Other (OTH) AF: 0.645 AC: 38835 AN: 60254

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

African (AFR) AF: 0.491 AC: 20367 AN: 41452

American (AMR) AF: 0.707 AC: 10811 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 2227 AN: 3472

East Asian (EAS) AF: 0.773 AC: 3962 AN: 5124

South Asian (SAS) AF: 0.565 AC: 2723 AN: 4818

European-Finnish (FIN) AF: 0.547 AC: 5789 AN: 10586

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.651 AC: 44227 AN: 67948

Other (OTH) AF: 0.652 AC: 1376 AN: 2112

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:1

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.3
DANN	Benign	0.73
PhyloP100		-0.37
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: rs494198; hg19: chr1-55518528;