1-55059726-C-T

Variant names:

• chr1-55059726-C-T
• rs45439391
• NM_174936.4:c.1681+63C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_174936.4(PCSK9):​c.1681+63C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0509 in 1,529,080 control chromosomes in the GnomAD database, including 2,203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (233 hom., cov: 33)
  • Exomes 𝑓: 0.051 (1970 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.486
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-55059726-C-T is Benign according to our data. Variant chr1-55059726-C-T is described in ClinVar as Benign. ClinVar VariationId is 265947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0595 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1681+63C>T		intron_variant	Intron 10 of 11	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.1681+63C>T		intron_variant	Intron 10 of 11	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.0520 AC: 7907 AN: 152204 Hom.: 233 Cov.: 33

Gnomad AFR AF: 0.0615

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0427

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.0511

Gnomad SAS AF: 0.0627

Gnomad FIN AF: 0.0164

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0491

Gnomad OTH AF: 0.0631

GnomAD4 exome AF: 0.0508 AC: 69982 AN: 1376758 Hom.: 1970 AF XY: 0.0514 AC XY: 34802 AN XY: 677392

African (AFR) AF: 0.0634 AC: 1974 AN: 31120

American (AMR) AF: 0.0345 AC: 1219 AN: 35330

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 2878 AN: 24536

East Asian (EAS) AF: 0.0416 AC: 1473 AN: 35428

South Asian (SAS) AF: 0.0625 AC: 4860 AN: 77770

European-Finnish (FIN) AF: 0.0231 AC: 1105 AN: 47800

Middle Eastern (MID) AF: 0.113 AC: 453 AN: 4022

European-Non Finnish (NFE) AF: 0.0496 AC: 52736 AN: 1063724

Other (OTH) AF: 0.0576 AC: 3284 AN: 57028

GnomAD4 genome AF: 0.0520 AC: 7916 AN: 152322 Hom.: 233 Cov.: 33 AF XY: 0.0501 AC XY: 3730 AN XY: 74488

African (AFR) AF: 0.0615 AC: 2557 AN: 41562

American (AMR) AF: 0.0427 AC: 653 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 396 AN: 3472

East Asian (EAS) AF: 0.0512 AC: 265 AN: 5172

South Asian (SAS) AF: 0.0623 AC: 301 AN: 4828

European-Finnish (FIN) AF: 0.0164 AC: 174 AN: 10624

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.0491 AC: 3339 AN: 68034

Other (OTH) AF: 0.0634 AC: 134 AN: 2114

Alfa AF: 0.0538 Hom.: 48

Bravo AF: 0.0552

Asia WGS AF: 0.0580 AC: 203 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:1

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.84
DANN	Benign	0.56
PhyloP100		-0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs45439391; hg19: chr1-55525399;