1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGT

Position:

• chr1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000302118.5(PCSK9):​c.1503+56_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 0.0088 (18 hom., cov: 0)
  • Exomes 𝑓: 0.18 (126 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCSK9 ENST00000302118.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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-CGTGTGTGTGTGTGTGT-C is Benign according to our data. Variant chr1-55058666-CGTGTGTGTGTGTGTGT-C is described in ClinVar as [Likely_benign]. Clinvar id is 492236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55058666-CGTGTGTGTGTGTGTGT-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00882 (1251/141802) while in subpopulation AFR AF= 0.0163 (617/37802). AF 95% confidence interval is 0.0153. There are 18 homozygotes in gnomad4. There are 612 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1251 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1503+56_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+56_1503+71del		intron_variant		1	NM_174936.4	ENSP00000303208	P2

Frequencies

GnomAD3 genomes AF: 0.00880 AC: 1247 AN: 141738 Hom.: 18 Cov.: 0

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.0955

Gnomad AMR AF: 0.00345

Gnomad ASJ AF: 0.00656

Gnomad EAS AF: 0.00885

Gnomad SAS AF: 0.00664

Gnomad FIN AF: 0.00814

Gnomad MID AF: 0.00676

Gnomad NFE AF: 0.00492

Gnomad OTH AF: 0.00569

GnomAD3 exomes AF: 0.176 AC: 26267 AN: 149146 Hom.: 82 AF XY: 0.173 AC XY: 14220 AN XY: 81986

Gnomad AFR exome AF: 0.0996

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.194

Gnomad EAS exome AF: 0.266

Gnomad SAS exome AF: 0.216

Gnomad FIN exome AF: 0.154

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.200

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.184 AC: 228375 AN: 1242002 Hom.: 126 AF XY: 0.187 AC XY: 114796 AN XY: 614944

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.203

Gnomad4 ASJ exome AF: 0.213

Gnomad4 EAS exome AF: 0.272

Gnomad4 SAS exome AF: 0.254

Gnomad4 FIN exome AF: 0.179

Gnomad4 NFE exome AF: 0.176

Gnomad4 OTH exome AF: 0.191

GnomAD4 genome AF: 0.00882 AC: 1251 AN: 141802 Hom.: 18 Cov.: 0 AF XY: 0.00892 AC XY: 612 AN XY: 68638

Gnomad4 AFR AF: 0.0163

Gnomad4 AMR AF: 0.00344

Gnomad4 ASJ AF: 0.00656

Gnomad4 EAS AF: 0.00929

Gnomad4 SAS AF: 0.00643

Gnomad4 FIN AF: 0.00814

Gnomad4 NFE AF: 0.00493

Gnomad4 OTH AF: 0.00566

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

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

Nov 23, 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. -

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;