1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Position:

• chr1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant summary

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

The ENST00000302118.5(PCSK9):​c.1503+66_1503+71del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,532,782 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 0)
  • Exomes 𝑓: 0.0018 (1 hom.)
• Consequence: PCSK9 ENST00000302118.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.181

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-CGTGTGT-C is Benign according to our data. Variant chr1-55058666-CGTGTGT-C is described in ClinVar as [Likely_benign]. Clinvar id is 1579070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-55058666-CGTGTGT-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 357 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1503+66_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+66_1503+71del		intron_variant		1	NM_174936.4	ENSP00000303208	P2

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 353 AN: 142420 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00477

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00158

Gnomad ASJ AF: 0.00654

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000228

Gnomad FIN AF: 0.00240

Gnomad MID AF: 0.00338

Gnomad NFE AF: 0.00149

Gnomad OTH AF: 0.00360

GnomAD4 exome AF: 0.00178 AC: 2477 AN: 1390282 Hom.: 1 AF XY: 0.00173 AC XY: 1196 AN XY: 689396

Gnomad4 AFR exome AF: 0.00616

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00480

Gnomad4 EAS exome AF: 0.000189

Gnomad4 SAS exome AF: 0.000640

Gnomad4 FIN exome AF: 0.00402

Gnomad4 NFE exome AF: 0.00163

Gnomad4 OTH exome AF: 0.00211

GnomAD4 genome AF: 0.00251 AC: 357 AN: 142500 Hom.: 2 Cov.: 0 AF XY: 0.00243 AC XY: 168 AN XY: 69038

Gnomad4 AFR AF: 0.00486

Gnomad4 AMR AF: 0.00158

Gnomad4 ASJ AF: 0.00654

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000229

Gnomad4 FIN AF: 0.00240

Gnomad4 NFE AF: 0.00149

Gnomad4 OTH AF: 0.00358

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 21, 2024

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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;