chr1-55039879-A-ACTGCTGCTGCTGCTG

Position:

• chr1-55039879-A-ACTGCTGCTGCTGCTG

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_174936.4(PCSK9):​c.51_65dup​(p.Leu19_Leu23dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PCSK9 NM_174936.4 inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.246

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.51_65dup	p.Leu19_Leu23dup	inframe_insertion	1/12	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.51_65dup	p.Leu19_Leu23dup	inframe_insertion	1/12	1	NM_174936.4	ENSP00000303208	P2
PCSK9	ENST00000710286.1	c.408_422dup	p.Leu138_Leu142dup	inframe_insertion	1/12			ENSP00000518176	A2
PCSK9	ENST00000673726.1	c.51_65dup	p.Leu19_Leu23dup	inframe_insertion, NMD_transcript_variant	1/6			ENSP00000501004
PCSK9	ENST00000673913.2	c.51_65dup	p.Leu19_Leu23dup	inframe_insertion, NMD_transcript_variant	1/12			ENSP00000501161

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

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: rs35574083; hg19: chr1-55505552;