rs624612

Variant names:

• chr1-55052210-C-G
• rs624612
• NM_174936.4:c.524-68C>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.524-68C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 1,603,938 control chromosomes in the GnomAD database, including 154,167 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 0.35 (11878 hom., cov: 32)
  • Exomes 𝑓: 0.43 (142289 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.30
• Publications: 11 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: Ambry Genetics, ClinGen, 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.696 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.524-68C>G		intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.647-68C>G		intron	N/A	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.524-68C>G		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.524-68C>G		intron	N/A	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.881-68C>G		intron	N/A	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.647-68C>G		intron	N/A	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53753 AN: 151908 Hom.: 11870 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.333

Gnomad EAS AF: 0.715

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.393

GnomAD4 exome AF: 0.433 AC: 628076 AN: 1451914 Hom.: 142289 Cov.: 30 AF XY: 0.430 AC XY: 310991 AN XY: 722824

African (AFR) AF: 0.0839 AC: 2791 AN: 33264

American (AMR) AF: 0.688 AC: 30740 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 8442 AN: 26066

East Asian (EAS) AF: 0.719 AC: 28492 AN: 39630

South Asian (SAS) AF: 0.415 AC: 35691 AN: 85952

European-Finnish (FIN) AF: 0.403 AC: 20865 AN: 51772

Middle Eastern (MID) AF: 0.327 AC: 1875 AN: 5736

European-Non Finnish (NFE) AF: 0.429 AC: 473493 AN: 1104666

Other (OTH) AF: 0.427 AC: 25687 AN: 60120

GnomAD4 genome AF: 0.354 AC: 53774 AN: 152024 Hom.: 11878 Cov.: 32 AF XY: 0.359 AC XY: 26673 AN XY: 74306

African (AFR) AF: 0.100 AC: 4163 AN: 41484

American (AMR) AF: 0.558 AC: 8532 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 1154 AN: 3470

East Asian (EAS) AF: 0.715 AC: 3676 AN: 5140

South Asian (SAS) AF: 0.431 AC: 2069 AN: 4804

European-Finnish (FIN) AF: 0.393 AC: 4152 AN: 10576

Middle Eastern (MID) AF: 0.223 AC: 65 AN: 292

European-Non Finnish (NFE) AF: 0.425 AC: 28856 AN: 67954

Other (OTH) AF: 0.397 AC: 838 AN: 2112

Alfa AF: 0.380 Hom.: 1691

Bravo AF: 0.359

Asia WGS AF: 0.546 AC: 1897 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.069
DANN	Benign	0.41
PhyloP100		-2.3
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs624612;

hg19: chr1-55517883;