chr1-55041976-C-T

Variant names:

• chr1-55041976-C-T
• rs11206513
• NM_174936.4:c.208-1867C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001407240.1(PCSK9):​c.217C>T​(p.Arg73Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 151,746 control chromosomes in the GnomAD database, including 23,437 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.53 (23437 hom., cov: 31)
• Consequence: PCSK9 NM_001407240.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.08

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=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.208-1867C>T		intron_variant	Intron 1 of 11	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.208-1867C>T		intron_variant	Intron 1 of 11	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80102 AN: 151626 Hom.: 23436 Cov.: 31

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.521

Gnomad AMR AF: 0.613

Gnomad ASJ AF: 0.555

Gnomad EAS AF: 0.820

Gnomad SAS AF: 0.670

Gnomad FIN AF: 0.725

Gnomad MID AF: 0.596

Gnomad NFE AF: 0.605

Gnomad OTH AF: 0.536

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

GnomAD4 genome AF: 0.528 AC: 80114 AN: 151746 Hom.: 23437 Cov.: 31 AF XY: 0.539 AC XY: 39988 AN XY: 74174

Gnomad4 AFR AF: 0.264

Gnomad4 AMR AF: 0.613

Gnomad4 ASJ AF: 0.555

Gnomad4 EAS AF: 0.820

Gnomad4 SAS AF: 0.670

Gnomad4 FIN AF: 0.725

Gnomad4 NFE AF: 0.605

Gnomad4 OTH AF: 0.538

Alfa AF: 0.556 Hom.: 3088

Bravo AF: 0.504

Asia WGS AF: 0.723 AC: 2513 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.79
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11206513; hg19: chr1-55507649;