rs2479413

Variant names:

• chr1-55053009-C-T
• rs2479413
• NM_174936.4:c.799+218C>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.799+218C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 152,054 control chromosomes in the GnomAD database, including 11,245 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 0.38 (11245 hom., cov: 33)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.277
• Publications: 9 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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 (AFR) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174936.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	NM_174936.4	MANE Select	c.799+218C>T		intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.922+218C>T		intron	N/A	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.799+218C>T		intron	N/A	NP_001394170.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.799+218C>T		intron	N/A	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.1156+218C>T		intron	N/A	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.922+218C>T		intron	N/A	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.376 AC: 57178 AN: 151936 Hom.: 11233 Cov.: 33

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.341

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

GnomAD4 genome AF: 0.376 AC: 57233 AN: 152054 Hom.: 11245 Cov.: 33 AF XY: 0.378 AC XY: 28088 AN XY: 74300

African (AFR) AF: 0.470 AC: 19464 AN: 41446

American (AMR) AF: 0.278 AC: 4248 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 1215 AN: 3466

East Asian (EAS) AF: 0.202 AC: 1043 AN: 5168

South Asian (SAS) AF: 0.431 AC: 2081 AN: 4824

European-Finnish (FIN) AF: 0.429 AC: 4532 AN: 10572

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.347 AC: 23584 AN: 67968

Other (OTH) AF: 0.340 AC: 718 AN: 2112

Alfa AF: 0.349 Hom.: 16090

Bravo AF: 0.366

Asia WGS AF: 0.320 AC: 1115 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.6
DANN	Benign	0.77
PhyloP100		-0.28
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: rs2479413; hg19: chr1-55518682;