1-55047322-G-A

Variant names:

• chr1-55047322-G-A
• rs2495478
• NM_174936.4:c.523+676G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_174936.4(PCSK9):​c.523+676G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 152,174 control chromosomes in the GnomAD database, including 1,949 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 0.12 (1949 hom., cov: 32)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.50
• Publications: 24 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.281 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.523+676G>A		intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.646+676G>A		intron	N/A	NP_001394169.1
	PCSK9	NM_001407241.1		c.523+676G>A		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.523+676G>A		intron	N/A	ENSP00000303208.5
	PCSK9	ENST00000673662.1		n.593G>A		non_coding_transcript_exon	Exon 3 of 3
	PCSK9	ENST00000710286.1		c.880+676G>A		intron	N/A	ENSP00000518176.1

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18425 AN: 152056 Hom.: 1941 Cov.: 32

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0671

Gnomad EAS AF: 0.0724

Gnomad SAS AF: 0.0284

Gnomad FIN AF: 0.0308

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0518

Gnomad OTH AF: 0.106

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

GnomAD4 genome AF: 0.121 AC: 18470 AN: 152174 Hom.: 1949 Cov.: 32 AF XY: 0.118 AC XY: 8792 AN XY: 74410

African (AFR) AF: 0.286 AC: 11848 AN: 41474

American (AMR) AF: 0.114 AC: 1736 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0671 AC: 233 AN: 3470

East Asian (EAS) AF: 0.0720 AC: 373 AN: 5180

South Asian (SAS) AF: 0.0280 AC: 135 AN: 4826

European-Finnish (FIN) AF: 0.0308 AC: 327 AN: 10618

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0518 AC: 3525 AN: 68000

Other (OTH) AF: 0.105 AC: 222 AN: 2106

Alfa AF: 0.0830 Hom.: 2413

Bravo AF: 0.138

Asia WGS AF: 0.0570 AC: 199 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.3
DANN	Benign	0.57
PhyloP100		1.5
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: rs2495478; hg19: chr1-55512995;