rs2479413

Positions:

• chr1-55053009-C-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.799+218C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 152,054 control chromosomes in the GnomAD database, including 11,245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency: Genomes: 𝑓 0.38 (11245 hom., cov: 33)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.277

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=-0.87).
• BP6: Variant 1-55053009-C-T is Benign according to our data. Variant chr1-55053009-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.799+218C>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.799+218C>T		intron_variant		1	NM_174936.4	ENSP00000303208	P2

Frequencies

GnomAD3 genomes AF: 0.376 AC: 57178 AN: 151936 Hom.: 11233 Cov.: 33

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.341

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

GnomAD4 genome AF: 0.376 AC: 57233 AN: 152054 Hom.: 11245 Cov.: 33 AF XY: 0.378 AC XY: 28088 AN XY: 74300

Gnomad4 AFR AF: 0.470

Gnomad4 AMR AF: 0.278

Gnomad4 ASJ AF: 0.351

Gnomad4 EAS AF: 0.202

Gnomad4 SAS AF: 0.431

Gnomad4 FIN AF: 0.429

Gnomad4 NFE AF: 0.347

Gnomad4 OTH AF: 0.340

Alfa AF: 0.344 Hom.: 10190

Bravo AF: 0.366

Asia WGS AF: 0.320 AC: 1115 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.6
DANN	Benign	0.77

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: rs2479413; hg19: chr1-55518682;