1-55051671-C-T

Variant names:

• chr1-55051671-C-T
• rs572512
• NM_174936.4:c.524-607C>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.524-607C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 203,198 control chromosomes in the GnomAD database, including 14,238 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 0.34 (10196 hom., cov: 32)
  • Exomes 𝑓: 0.37 (4042 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.23
• Publications: 19 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.524-607C>T		intron_variant	Intron 3 of 11	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.524-607C>T		intron_variant	Intron 3 of 11	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52382 AN: 151918 Hom.: 10182 Cov.: 32

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.496

Gnomad ASJ AF: 0.345

Gnomad EAS AF: 0.764

Gnomad SAS AF: 0.443

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.378

GnomAD4 exome AF: 0.373 AC: 19064 AN: 51160 Hom.: 4042 Cov.: 0 AF XY: 0.379 AC XY: 10022 AN XY: 26430

African (AFR) AF: 0.206 AC: 129 AN: 626

American (AMR) AF: 0.517 AC: 1847 AN: 3574

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 288 AN: 890

East Asian (EAS) AF: 0.763 AC: 1585 AN: 2078

South Asian (SAS) AF: 0.412 AC: 3073 AN: 7464

European-Finnish (FIN) AF: 0.317 AC: 716 AN: 2260

Middle Eastern (MID) AF: 0.307 AC: 46 AN: 150

European-Non Finnish (NFE) AF: 0.331 AC: 10440 AN: 31532

Other (OTH) AF: 0.363 AC: 940 AN: 2586

GnomAD4 genome AF: 0.345 AC: 52427 AN: 152038 Hom.: 10196 Cov.: 32 AF XY: 0.348 AC XY: 25862 AN XY: 74302

African (AFR) AF: 0.218 AC: 9063 AN: 41494

American (AMR) AF: 0.497 AC: 7581 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 1197 AN: 3472

East Asian (EAS) AF: 0.764 AC: 3940 AN: 5158

South Asian (SAS) AF: 0.444 AC: 2137 AN: 4808

European-Finnish (FIN) AF: 0.311 AC: 3281 AN: 10564

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.354 AC: 24028 AN: 67952

Other (OTH) AF: 0.384 AC: 813 AN: 2116

Alfa AF: 0.353 Hom.: 14150

Bravo AF: 0.356

Asia WGS AF: 0.583 AC: 2025 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.6
DANN	Benign	0.77
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs572512; hg19: chr1-55517344;