rs630431

Positions:

• chr1-55061650-G-A
• chr1-55061650-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_174936.4(PCSK9):​c.1863+94G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.697 in 1,476,310 control chromosomes in the GnomAD database, including 363,586 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.63 (32425 hom., cov: 32)
  • Exomes 𝑓: 0.70 (331161 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0410

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-55061650-G-A is Benign according to our data. Variant chr1-55061650-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1863+94G>A		intron_variant		ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.1863+94G>A		intron_variant		1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96408 AN: 151900 Hom.: 32422 Cov.: 32

Gnomad AFR AF: 0.401

Gnomad AMI AF: 0.708

Gnomad AMR AF: 0.777

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.857

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.714

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.705

Gnomad OTH AF: 0.682

GnomAD4 exome AF: 0.704 AC: 932420 AN: 1324290 Hom.: 331161 AF XY: 0.706 AC XY: 463953 AN XY: 656862

Gnomad4 AFR exome AF: 0.381

Gnomad4 AMR exome AF: 0.828

Gnomad4 ASJ exome AF: 0.625

Gnomad4 EAS exome AF: 0.859

Gnomad4 SAS exome AF: 0.751

Gnomad4 FIN exome AF: 0.717

Gnomad4 NFE exome AF: 0.702

Gnomad4 OTH exome AF: 0.690

GnomAD4 genome AF: 0.634 AC: 96431 AN: 152020 Hom.: 32425 Cov.: 32 AF XY: 0.641 AC XY: 47641 AN XY: 74316

Gnomad4 AFR AF: 0.400

Gnomad4 AMR AF: 0.777

Gnomad4 ASJ AF: 0.629

Gnomad4 EAS AF: 0.857

Gnomad4 SAS AF: 0.764

Gnomad4 FIN AF: 0.714

Gnomad4 NFE AF: 0.705

Gnomad4 OTH AF: 0.684

Alfa AF: 0.565 Hom.: 2485

Bravo AF: 0.628

Asia WGS AF: 0.769 AC: 2674 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.63
DANN	Benign	0.87

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

Publications

LitVar

Other links and lift over

dbSNP: rs630431; hg19: chr1-55527323; COSMIC: COSV53764048; COSMIC: COSV53764048;