rs613855

Variant names:

• chr1-55052188-C-G
• rs613855
• NM_174936.4:c.524-90C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-55052188-C-G
• chr1-55052188-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_174936.4(PCSK9):​c.524-90C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 1,568,736 control chromosomes in the GnomAD database, including 187,046 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.42 (15237 hom., cov: 31)
  • Exomes 𝑓: 0.48 (171809 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.524-90C>G		intron_variant	Intron 3 of 11	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.524-90C>G		intron_variant	Intron 3 of 11	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64302 AN: 151760 Hom.: 15229 Cov.: 31

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.605

Gnomad ASJ AF: 0.440

Gnomad EAS AF: 0.767

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.467

GnomAD4 exome AF: 0.485 AC: 687062 AN: 1416856 Hom.: 171809 Cov.: 25 AF XY: 0.482 AC XY: 340886 AN XY: 707502

African (AFR) AF: 0.218 AC: 7056 AN: 32410

American (AMR) AF: 0.724 AC: 32321 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 11299 AN: 25864

East Asian (EAS) AF: 0.763 AC: 30097 AN: 39446

South Asian (SAS) AF: 0.454 AC: 38557 AN: 84998

European-Finnish (FIN) AF: 0.429 AC: 21405 AN: 49884

Middle Eastern (MID) AF: 0.458 AC: 2564 AN: 5594

European-Non Finnish (NFE) AF: 0.479 AC: 514984 AN: 1075092

Other (OTH) AF: 0.488 AC: 28779 AN: 58938

GnomAD4 genome AF: 0.424 AC: 64339 AN: 151880 Hom.: 15237 Cov.: 31 AF XY: 0.426 AC XY: 31615 AN XY: 74222

African (AFR) AF: 0.229 AC: 9493 AN: 41412

American (AMR) AF: 0.606 AC: 9258 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 1527 AN: 3468

East Asian (EAS) AF: 0.767 AC: 3941 AN: 5138

South Asian (SAS) AF: 0.471 AC: 2265 AN: 4814

European-Finnish (FIN) AF: 0.412 AC: 4343 AN: 10546

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.473 AC: 32111 AN: 67908

Other (OTH) AF: 0.471 AC: 996 AN: 2114

Alfa AF: 0.330 Hom.: 1058

Bravo AF: 0.435

Asia WGS AF: 0.602 AC: 2092 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.79
DANN	Benign	0.60
PhyloP100		-1.0
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: rs613855; hg19: chr1-55517861;