1-55060623-A-G

Variant names:

• chr1-55060623-A-G
• rs615563
• NM_174936.4:c.1682-752A>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.1682-752A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.638 in 152,002 control chromosomes in the GnomAD database, including 32,656 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 0.64 (32656 hom., cov: 31)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.741
• Publications: 15 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.842 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1682-752A>G		intron_variant	Intron 10 of 11	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.1682-752A>G		intron_variant	Intron 10 of 11	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.638 AC: 96945 AN: 151882 Hom.: 32653 Cov.: 31

Gnomad AFR AF: 0.413

Gnomad AMI AF: 0.708

Gnomad AMR AF: 0.779

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.863

Gnomad SAS AF: 0.766

Gnomad FIN AF: 0.718

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.703

Gnomad OTH AF: 0.688

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

GnomAD4 genome AF: 0.638 AC: 96979 AN: 152002 Hom.: 32656 Cov.: 31 AF XY: 0.645 AC XY: 47929 AN XY: 74280

African (AFR) AF: 0.412 AC: 17086 AN: 41426

American (AMR) AF: 0.780 AC: 11929 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.629 AC: 2185 AN: 3472

East Asian (EAS) AF: 0.863 AC: 4441 AN: 5144

South Asian (SAS) AF: 0.766 AC: 3686 AN: 4814

European-Finnish (FIN) AF: 0.718 AC: 7582 AN: 10556

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.703 AC: 47774 AN: 67972

Other (OTH) AF: 0.690 AC: 1459 AN: 2114

Alfa AF: 0.671 Hom.: 15822

Bravo AF: 0.632

Asia WGS AF: 0.777 AC: 2702 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.082
DANN	Benign	0.31
PhyloP100		-0.74
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: rs615563; hg19: chr1-55526296; COSMIC: COSV56161338;