rs2479412

Variant names:

• chr1-55048400-C-G
• rs2479412
• NM_174936.4:c.523+1754C>G

Variant summary

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

The NM_174936.4(PCSK9):​c.523+1754C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.086 in 152,292 control chromosomes in the GnomAD database, including 776 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 0.086 (776 hom., cov: 34)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.133
• Publications: 5 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.523+1754C>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.523+1754C>G		intron_variant	Intron 3 of 11	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.0859 AC: 13067 AN: 152174 Hom.: 772 Cov.: 34

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.0671

Gnomad EAS AF: 0.0723

Gnomad SAS AF: 0.0282

Gnomad FIN AF: 0.0305

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0511

Gnomad OTH AF: 0.0803

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0860 AC: 13093 AN: 152292 Hom.: 776 Cov.: 34 AF XY: 0.0843 AC XY: 6282 AN XY: 74476

African (AFR) AF: 0.163 AC: 6760 AN: 41538

American (AMR) AF: 0.101 AC: 1550 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0671 AC: 233 AN: 3470

East Asian (EAS) AF: 0.0719 AC: 373 AN: 5186

South Asian (SAS) AF: 0.0282 AC: 136 AN: 4818

European-Finnish (FIN) AF: 0.0305 AC: 324 AN: 10628

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0511 AC: 3477 AN: 68030

Other (OTH) AF: 0.0799 AC: 169 AN: 2114

Alfa AF: 0.0745 Hom.: 77

Bravo AF: 0.0980

Asia WGS AF: 0.0500 AC: 174 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.6
DANN	Benign	0.75
PhyloP100		0.13
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: rs2479412; hg19: chr1-55514073;