1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Position:

• chr1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant summary

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

The NM_174936.4(PCSK9):​c.1503+70_1503+71dupGT 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 0.019 (30 hom., cov: 0)
  • Exomes 𝑓: 0.0045 (4 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.20

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-C-CGT is Benign according to our data. Variant chr1-55058666-C-CGT is described in ClinVar as [Likely_benign]. Clinvar id is 928570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0187 (2662/142256) while in subpopulation SAS AF= 0.0232 (101/4362). AF 95% confidence interval is 0.0215. There are 30 homozygotes in gnomad4. There are 1228 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2662 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1503+70_1503+71dupGT		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+19_1503+20insGT		intron_variant		1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2658 AN: 142178 Hom.: 30 Cov.: 0

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.00341

Gnomad AMR AF: 0.00961

Gnomad ASJ AF: 0.0295

Gnomad EAS AF: 0.000631

Gnomad SAS AF: 0.0227

Gnomad FIN AF: 0.00733

Gnomad MID AF: 0.0203

Gnomad NFE AF: 0.0208

Gnomad OTH AF: 0.0149

GnomAD4 exome AF: 0.00453 AC: 6264 AN: 1382268 Hom.: 4 Cov.: 0 AF XY: 0.00479 AC XY: 3282 AN XY: 685196

Gnomad4 AFR exome AF: 0.00741

Gnomad4 AMR exome AF: 0.00408

Gnomad4 ASJ exome AF: 0.00962

Gnomad4 EAS exome AF: 0.00157

Gnomad4 SAS exome AF: 0.00986

Gnomad4 FIN exome AF: 0.00350

Gnomad4 NFE exome AF: 0.00400

Gnomad4 OTH exome AF: 0.00604

GnomAD4 genome AF: 0.0187 AC: 2662 AN: 142256 Hom.: 30 Cov.: 0 AF XY: 0.0178 AC XY: 1228 AN XY: 68908

Gnomad4 AFR AF: 0.0228

Gnomad4 AMR AF: 0.00960

Gnomad4 ASJ AF: 0.0295

Gnomad4 EAS AF: 0.000633

Gnomad4 SAS AF: 0.0232

Gnomad4 FIN AF: 0.00733

Gnomad4 NFE AF: 0.0208

Gnomad4 OTH AF: 0.0148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 09, 2019

Variant summary: PCSK9 c.1503+68_1503+69dupGT is located at a position not widely known to affect splicing. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.019 in 24890 control chromosomes, predominantly at a frequency of 0.024 within the African or African-American subpopulation in the gnomAD database, including 10 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 256-folds over the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (9.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.1503+68_1503+69dupGT in individuals affected with Familial Hypercholesterolemia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

Hypercholesterolemia, autosomal dominant, 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 13, 2023

- -

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;