1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGT

Position:

• chr1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000302118.5(PCSK9):​c.1503+58_1503+71del variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (31090 hom., cov: 0)
  • Exomes 𝑓: 0.45 (20384 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCSK9 ENST00000302118.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.564

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 -16 ACMG points.

• BP6: Variant 1-55058666-CGTGTGTGTGTGTGT-C is Benign according to our data. Variant chr1-55058666-CGTGTGTGTGTGTGT-C is described in ClinVar as [Likely_benign]. Clinvar id is 492237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55058666-CGTGTGTGTGTGTGT-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.797 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1503+58_1503+71del		intron_variant		ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.1503+58_1503+71del		intron_variant		1	NM_174936.4	ENSP00000303208	P2

Frequencies

GnomAD3 genomes AF: 0.656 AC: 93337 AN: 142312 Hom.: 31100 Cov.: 0

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.624

Gnomad AMR AF: 0.710

Gnomad ASJ AF: 0.722

Gnomad EAS AF: 0.819

Gnomad SAS AF: 0.807

Gnomad FIN AF: 0.658

Gnomad MID AF: 0.767

Gnomad NFE AF: 0.691

Gnomad OTH AF: 0.724

GnomAD3 exomes AF: 0.302 AC: 45000 AN: 149146 Hom.: 1993 AF XY: 0.294 AC XY: 24102 AN XY: 81986

Gnomad AFR exome AF: 0.250

Gnomad AMR exome AF: 0.333

Gnomad ASJ exome AF: 0.310

Gnomad EAS exome AF: 0.391

Gnomad SAS exome AF: 0.314

Gnomad FIN exome AF: 0.342

Gnomad NFE exome AF: 0.262

Gnomad OTH exome AF: 0.333

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.450 AC: 625650 AN: 1388816 Hom.: 20384 AF XY: 0.448 AC XY: 308553 AN XY: 688620

Gnomad4 AFR exome AF: 0.371

Gnomad4 AMR exome AF: 0.419

Gnomad4 ASJ exome AF: 0.448

Gnomad4 EAS exome AF: 0.473

Gnomad4 SAS exome AF: 0.454

Gnomad4 FIN exome AF: 0.434

Gnomad4 NFE exome AF: 0.454

Gnomad4 OTH exome AF: 0.451

GnomAD4 genome AF: 0.656 AC: 93348 AN: 142392 Hom.: 31090 Cov.: 0 AF XY: 0.659 AC XY: 45475 AN XY: 68972

Gnomad4 AFR AF: 0.526

Gnomad4 AMR AF: 0.709

Gnomad4 ASJ AF: 0.722

Gnomad4 EAS AF: 0.819

Gnomad4 SAS AF: 0.806

Gnomad4 FIN AF: 0.658

Gnomad4 NFE AF: 0.691

Gnomad4 OTH AF: 0.726

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hypercholesterolemia, familial, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Aug 28, 2017

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial hypercholesterolemia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Aug 05, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35115360; hg19: chr1-55524339;