NM_174936.4:c.799+288C>T

Variant names:

• chr1-55053079-C-T
• rs7552841
• NM_174936.4:c.799+288C>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+288C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 151,954 control chromosomes in the GnomAD database, including 8,317 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 0.32 (8317 hom., cov: 31)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.751
• Publications: 37 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.377 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.799+288C>T		intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.922+288C>T		intron	N/A	NP_001394169.1
	PCSK9	NM_001407241.1		c.799+288C>T		intron	N/A	NP_001394170.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.799+288C>T		intron	N/A	ENSP00000303208.5
	PCSK9	ENST00000710286.1		c.1156+288C>T		intron	N/A	ENSP00000518176.1
	PCSK9	ENST00000713786.1		c.922+288C>T		intron	N/A	ENSP00000519088.1

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48764 AN: 151834 Hom.: 8317 Cov.: 31

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.402

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.362

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

GnomAD4 genome AF: 0.321 AC: 48770 AN: 151954 Hom.: 8317 Cov.: 31 AF XY: 0.318 AC XY: 23628 AN XY: 74268

African (AFR) AF: 0.237 AC: 9830 AN: 41420

American (AMR) AF: 0.322 AC: 4919 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1349 AN: 3468

East Asian (EAS) AF: 0.173 AC: 889 AN: 5148

South Asian (SAS) AF: 0.311 AC: 1500 AN: 4828

European-Finnish (FIN) AF: 0.300 AC: 3163 AN: 10548

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.381 AC: 25908 AN: 67956

Other (OTH) AF: 0.359 AC: 756 AN: 2106

Alfa AF: 0.357 Hom.: 17828

Bravo AF: 0.316

Asia WGS AF: 0.244 AC: 847 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.4
DANN	Benign	0.61
PhyloP100		-0.75
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: rs7552841; hg19: chr1-55518752;