1-55052517-ACC-ACCC

Position:

• chr1-55052517-ACC-ACCC

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_174936.4(PCSK9):​c.657+114dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0055 (5 hom., cov: 0)
  • Exomes 𝑓: 0.0068 (52 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.574

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00549 (831/151504) while in subpopulation SAS AF= 0.02 (96/4802). AF 95% confidence interval is 0.0168. There are 5 homozygotes in gnomad4. There are 455 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 831 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.657+114dupC		intron_variant		ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.657+114dupC		intron_variant		1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.00550 AC: 832 AN: 151386 Hom.: 5 Cov.: 0

Gnomad AFR AF: 0.00156

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00446

Gnomad ASJ AF: 0.00953

Gnomad EAS AF: 0.000585

Gnomad SAS AF: 0.0198

Gnomad FIN AF: 0.00511

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00738

Gnomad OTH AF: 0.00528

GnomAD4 exome AF: 0.00682 AC: 9848 AN: 1444146 Hom.: 52 Cov.: 0 AF XY: 0.00730 AC XY: 5234 AN XY: 717124

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00428

Gnomad4 ASJ exome AF: 0.00764

Gnomad4 EAS exome AF: 0.0000764

Gnomad4 SAS exome AF: 0.0182

Gnomad4 FIN exome AF: 0.00513

Gnomad4 NFE exome AF: 0.00652

Gnomad4 OTH exome AF: 0.00646

GnomAD4 genome AF: 0.00549 AC: 831 AN: 151504 Hom.: 5 Cov.: 0 AF XY: 0.00614 AC XY: 455 AN XY: 74068

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00445

Gnomad4 ASJ AF: 0.00953

Gnomad4 EAS AF: 0.000586

Gnomad4 SAS AF: 0.0200

Gnomad4 FIN AF: 0.00511

Gnomad4 NFE AF: 0.00738

Gnomad4 OTH AF: 0.00523

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs397735050; hg19: chr1-55518190;