1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGT

Variant names:

• chr1-55058666-CGTGTGTGTGTGTGT-C
• rs35115360
• NM_174936.4:c.1503+58_1503+71delGTGTGTGTGTGTGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_174936.4(PCSK9):​c.1503+58_1503+71delGTGTGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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 NM_174936.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.564
• Publications: 1 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 -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 Benign/Likely_benign. ClinVar VariationId is 492237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1503+58_1503+71delGTGTGTGTGTGTGT		intron_variant	Intron 9 of 11	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.1503+20_1503+33delGTGTGTGTGTGTGT		intron_variant	Intron 9 of 11	1	NM_174936.4	ENSP00000303208.5

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

GnomAD2 exomes AF: 0.302 AC: 45000 AN: 149146 AF XY: 0.294

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 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

African (AFR) AF: 0.371 AC: 11667 AN: 31462

American (AMR) AF: 0.419 AC: 16509 AN: 39370

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 11113 AN: 24806

East Asian (EAS) AF: 0.473 AC: 17409 AN: 36824

South Asian (SAS) AF: 0.454 AC: 36859 AN: 81212

European-Finnish (FIN) AF: 0.434 AC: 20714 AN: 47776

Middle Eastern (MID) AF: 0.477 AC: 1910 AN: 4008

European-Non Finnish (NFE) AF: 0.454 AC: 483575 AN: 1065950

Other (OTH) AF: 0.451 AC: 25894 AN: 57408

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

African (AFR) AF: 0.526 AC: 19889 AN: 37822

American (AMR) AF: 0.709 AC: 10351 AN: 14592

Ashkenazi Jewish (ASJ) AF: 0.722 AC: 2428 AN: 3362

East Asian (EAS) AF: 0.819 AC: 3877 AN: 4736

South Asian (SAS) AF: 0.806 AC: 3524 AN: 4370

European-Finnish (FIN) AF: 0.658 AC: 6019 AN: 9148

Middle Eastern (MID) AF: 0.765 AC: 208 AN: 272

European-Non Finnish (NFE) AF: 0.691 AC: 45082 AN: 65252

Other (OTH) AF: 0.726 AC: 1421 AN: 1958

Alfa AF: 0.444 Hom.: 1122

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypercholesterolemia, familial, 1 Benign:1

Aug 28, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Nov 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Oct 27, 2016

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 05, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.56
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs35115360; hg19: chr1-55524339; COSMIC: COSV56163361;