1-55051671-C-T

Position:

• chr1-55051671-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.524-607C>T		intron_variant		ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.524-607C>T		intron_variant		1	NM_174936.4	ENSP00000303208	P2

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

Gnomad4 AFR exome AF: 0.206

Gnomad4 AMR exome AF: 0.517

Gnomad4 ASJ exome AF: 0.324

Gnomad4 EAS exome AF: 0.763

Gnomad4 SAS exome AF: 0.412

Gnomad4 FIN exome AF: 0.317

Gnomad4 NFE exome AF: 0.331

Gnomad4 OTH exome AF: 0.363

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

Gnomad4 AFR AF: 0.218

Gnomad4 AMR AF: 0.497

Gnomad4 ASJ AF: 0.345

Gnomad4 EAS AF: 0.764

Gnomad4 SAS AF: 0.444

Gnomad4 FIN AF: 0.311

Gnomad4 NFE AF: 0.354

Gnomad4 OTH AF: 0.384

Alfa AF: 0.349 Hom.: 9140

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs572512; hg19: chr1-55517344;