1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGT

Variant names:

• chr1-55058666-CGTGTGTGTGTGTGTGT-C
• rs35115360
• NM_174936.4:c.1503+56_1503+71delGTGTGTGTGTGTGTGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_174936.4(PCSK9):​c.1503+56_1503+71delGTGTGTGTGTGTGTGT 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 0.0088 (18 hom., cov: 0)
  • Exomes 𝑓: 0.18 (126 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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-CGTGTGTGTGTGTGTGT-C is Benign according to our data. Variant chr1-55058666-CGTGTGTGTGTGTGTGT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 492236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1503+56_1503+71delGTGTGTGTGTGTGTGT		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+35delGTGTGTGTGTGTGTGT		intron_variant	Intron 9 of 11	1	NM_174936.4	ENSP00000303208.5

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

GnomAD2 exomes AF: 0.176 AC: 26267 AN: 149146 AF XY: 0.173

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.112 AC: 3348 AN: 29770

American (AMR) AF: 0.203 AC: 7307 AN: 35994

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 4769 AN: 22370

East Asian (EAS) AF: 0.272 AC: 8746 AN: 32140

South Asian (SAS) AF: 0.254 AC: 17935 AN: 70624

European-Finnish (FIN) AF: 0.179 AC: 7844 AN: 43914

Middle Eastern (MID) AF: 0.250 AC: 871 AN: 3490

European-Non Finnish (NFE) AF: 0.176 AC: 167768 AN: 952330

Other (OTH) AF: 0.191 AC: 9787 AN: 51370

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.0163 AC: 617 AN: 37802

American (AMR) AF: 0.00344 AC: 50 AN: 14526

Ashkenazi Jewish (ASJ) AF: 0.00656 AC: 22 AN: 3352

East Asian (EAS) AF: 0.00929 AC: 44 AN: 4736

South Asian (SAS) AF: 0.00643 AC: 28 AN: 4352

European-Finnish (FIN) AF: 0.00814 AC: 72 AN: 8842

Middle Eastern (MID) AF: 0.00735 AC: 2 AN: 272

European-Non Finnish (NFE) AF: 0.00493 AC: 321 AN: 65096

Other (OTH) AF: 0.00566 AC: 11 AN: 1944

Alfa AF: 0.135 Hom.: 1122

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

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 27, 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

Nov 23, 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. -

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;