1-55041976-C-T

Variant names:

• chr1-55041976-C-T
• rs11206513
• NM_174936.4:c.208-1867C>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.208-1867C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 151,746 control chromosomes in the GnomAD database, including 23,437 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 0.53 (23437 hom., cov: 31)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.08
• 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=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.8 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	NM_174936.4	MANE Select	c.208-1867C>T		intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.217C>T	p.Arg73Cys	missense	Exon 2 of 13	NP_001394169.1
	PCSK9	NR_176320.1		n.507C>T		non_coding_transcript_exon	Exon 2 of 13

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.208-1867C>T		intron	N/A	ENSP00000303208.5
	PCSK9	ENST00000713786.1		c.217C>T	p.Arg73Cys	missense	Exon 2 of 13	ENSP00000519088.1
	PCSK9	ENST00000710286.1		c.565-1867C>T		intron	N/A	ENSP00000518176.1

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80102 AN: 151626 Hom.: 23436 Cov.: 31

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.521

Gnomad AMR AF: 0.613

Gnomad ASJ AF: 0.555

Gnomad EAS AF: 0.820

Gnomad SAS AF: 0.670

Gnomad FIN AF: 0.725

Gnomad MID AF: 0.596

Gnomad NFE AF: 0.605

Gnomad OTH AF: 0.536

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

GnomAD4 genome AF: 0.528 AC: 80114 AN: 151746 Hom.: 23437 Cov.: 31 AF XY: 0.539 AC XY: 39988 AN XY: 74174

African (AFR) AF: 0.264 AC: 10913 AN: 41302

American (AMR) AF: 0.613 AC: 9345 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.555 AC: 1926 AN: 3470

East Asian (EAS) AF: 0.820 AC: 4244 AN: 5174

South Asian (SAS) AF: 0.670 AC: 3219 AN: 4808

European-Finnish (FIN) AF: 0.725 AC: 7637 AN: 10538

Middle Eastern (MID) AF: 0.586 AC: 171 AN: 292

European-Non Finnish (NFE) AF: 0.605 AC: 41054 AN: 67898

Other (OTH) AF: 0.538 AC: 1133 AN: 2104

Alfa AF: 0.556 Hom.: 3088

Bravo AF: 0.504

Asia WGS AF: 0.723 AC: 2513 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.79
DANN	Benign	0.74
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11206513; hg19: chr1-55507649;