1-55039507-C-T

Variant names:

• chr1-55039507-C-T
• rs778796405
• ENST00000710286.1:c.27C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The ENST00000710286.1(PCSK9):​c.27C>T​(p.Arg9Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 290,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R9R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PCSK9 ENST00000710286.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.65
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP7: Synonymous conserved (PhyloP=-1.65 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000710286.1. 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.-331C>T		upstream_gene	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.-331C>T		upstream_gene	N/A	NP_001394169.1
	PCSK9	NM_001407241.1		c.-331C>T		upstream_gene	N/A	NP_001394170.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000710286.1		c.27C>T	p.Arg9Arg	synonymous	Exon 1 of 12	ENSP00000518176.1
	PCSK9	ENST00000673726.2		n.-331C>T		non_coding_transcript_exon	Exon 1 of 13	ENSP00000501004.1
	PCSK9	ENST00000673913.2		n.-331C>T		non_coding_transcript_exon	Exon 1 of 12	ENSP00000501161.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000344 AC: 1 AN: 290704 Hom.: 0 Cov.: 0 AF XY: 0.00000664 AC XY: 1 AN XY: 150678

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 7504

American (AMR) AF: 0.00 AC: 0 AN: 11052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9134

East Asian (EAS) AF: 0.00 AC: 0 AN: 18346

South Asian (SAS) AF: 0.00 AC: 0 AN: 29636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18726

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1332

European-Non Finnish (NFE) AF: 0.00000564 AC: 1 AN: 177394

Other (OTH) AF: 0.00 AC: 0 AN: 17580

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.3
DANN	Benign	0.96
PhyloP100		-1.7
PromoterAI		0.00050	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs778796405; hg19: chr1-55505180;