rs28362286

Variant names:

• chr1-55063542-C-A
• rs28362286
• NM_174936.4:c.2037C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-55063542-C-A
• chr1-55063542-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PVS1_Moderate BS1 BS2

The NM_174936.4(PCSK9):​c.2037C>A​(p.Cys679*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000444 in 1,613,110 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. C679C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: PCSK9 NM_174936.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4 B:4 O:1
• Conservation: PhyloP100: 0.777
• Publications: 123 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: Likely_benign. The variant received -6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0202 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00236 (359/152360) while in subpopulation AFR AF = 0.00849 (353/41592). AF 95% confidence interval is 0.00776. There are 2 homozygotes in GnomAd4. There are 162 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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.2037C>A	p.Cys679*	stop_gained	Exon 12 of 12	NP_777596.2
	PCSK9	NM_001407240.1		c.2160C>A	p.Cys720*	stop_gained	Exon 13 of 13	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.2079C>A	p.Cys693*	stop_gained	Exon 12 of 12	NP_001394170.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.2037C>A	p.Cys679*	stop_gained	Exon 12 of 12	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.2394C>A	p.Cys798*	stop_gained	Exon 12 of 12	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.2160C>A	p.Cys720*	stop_gained	Exon 13 of 13	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.00234 AC: 357 AN: 152242 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00846

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000560 AC: 139 AN: 248284 AF XY: 0.000386

Gnomad AFR exome AF: 0.00805

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000244 AC: 357 AN: 1460750 Hom.: 2 Cov.: 33 AF XY: 0.000195 AC XY: 142 AN XY: 726724

African (AFR) AF: 0.00921 AC: 308 AN: 33444

American (AMR) AF: 0.000246 AC: 11 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53238

Middle Eastern (MID) AF: 0.000186 AC: 1 AN: 5380

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111698

Other (OTH) AF: 0.000481 AC: 29 AN: 60310

GnomAD4 genome AF: 0.00236 AC: 359 AN: 152360 Hom.: 2 Cov.: 33 AF XY: 0.00217 AC XY: 162 AN XY: 74490

African (AFR) AF: 0.00849 AC: 353 AN: 41592

American (AMR) AF: 0.000131 AC: 2 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000676 Hom.: 0

Bravo AF: 0.00255

ESP6500AA AF: 0.00841 AC: 37

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000767 AC: 93

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hypercholesterolemia, autosomal dominant, 3 (2)
1	1	-	not provided (2)
-	1	1	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Familial hypercholesterolemia (1)
1	-	-	Hypocholesterolemia (1)
-	1	-	PCSK9-related disorder (1)
-	-	-	Low density lipoprotein cholesterol level quantitative trait locus 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.81	D
PhyloP100		0.78
Vest4		0.83
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=25/175	disease causing (ClinVar)

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: rs28362286; hg19: chr1-55529215;