1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Position:

• chr1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The ENST00000302118.5(PCSK9):​c.1503+64_1503+71dup 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 0.0012 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: PCSK9 ENST00000302118.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 1-55058666-C-CGTGTGTGT is Benign according to our data. Variant chr1-55058666-C-CGTGTGTGT is described in ClinVar as [Likely_benign]. Clinvar id is 1621636.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 168 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1503+64_1503+71dup		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+64_1503+71dup		intron_variant		1	NM_174936.4	ENSP00000303208	P2

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 169 AN: 142430 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000715

Gnomad AMI AF: 0.00227

Gnomad AMR AF: 0.000823

Gnomad ASJ AF: 0.00208

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00114

Gnomad FIN AF: 0.000546

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.000514

GnomAD4 exome AF: 0.000345 AC: 481 AN: 1392412 Hom.: 0 Cov.: 0 AF XY: 0.000343 AC XY: 237 AN XY: 690438

Gnomad4 AFR exome AF: 0.000158

Gnomad4 AMR exome AF: 0.000379

Gnomad4 ASJ exome AF: 0.000322

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000983

Gnomad4 FIN exome AF: 0.000354

Gnomad4 NFE exome AF: 0.000379

Gnomad4 OTH exome AF: 0.000382

GnomAD4 genome AF: 0.00118 AC: 168 AN: 142510 Hom.: 1 Cov.: 0 AF XY: 0.00120 AC XY: 83 AN XY: 69042

Gnomad4 AFR AF: 0.000713

Gnomad4 AMR AF: 0.000822

Gnomad4 ASJ AF: 0.00208

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000915

Gnomad4 FIN AF: 0.000546

Gnomad4 NFE AF: 0.00168

Gnomad4 OTH AF: 0.000511

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 14, 2024

- -

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;