1-55052517-ACC-AC

Variant names:

• chr1-55052517-AC-A
• rs397735050
• NM_174936.4:c.657+114delC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_174936.4(PCSK9):​c.657+114delC variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.55 (26536 hom., cov: 0)
  • Exomes 𝑓: 0.67 (333988 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.574
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, autosomal dominant, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.657+114delC		intron_variant	Intron 4 of 11	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.657+107delC		intron_variant	Intron 4 of 11	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.554 AC: 83803 AN: 151308 Hom.: 26533 Cov.: 0

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.664

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.747

Gnomad SAS AF: 0.591

Gnomad FIN AF: 0.767

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.678

Gnomad OTH AF: 0.565

GnomAD4 exome AF: 0.675 AC: 974188 AN: 1443460 Hom.: 333988 Cov.: 0 AF XY: 0.672 AC XY: 481372 AN XY: 716754

African (AFR) AF: 0.202 AC: 6612 AN: 32776

American (AMR) AF: 0.705 AC: 30939 AN: 43892

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 14519 AN: 25778

East Asian (EAS) AF: 0.736 AC: 28901 AN: 39282

South Asian (SAS) AF: 0.585 AC: 49814 AN: 85216

European-Finnish (FIN) AF: 0.753 AC: 38664 AN: 51376

Middle Eastern (MID) AF: 0.533 AC: 2968 AN: 5566

European-Non Finnish (NFE) AF: 0.694 AC: 763125 AN: 1099972

Other (OTH) AF: 0.648 AC: 38646 AN: 59602

GnomAD4 genome AF: 0.554 AC: 83824 AN: 151426 Hom.: 26536 Cov.: 0 AF XY: 0.563 AC XY: 41653 AN XY: 74028

African (AFR) AF: 0.224 AC: 9182 AN: 41054

American (AMR) AF: 0.664 AC: 10140 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 1977 AN: 3460

East Asian (EAS) AF: 0.747 AC: 3819 AN: 5114

South Asian (SAS) AF: 0.592 AC: 2838 AN: 4794

European-Finnish (FIN) AF: 0.767 AC: 8104 AN: 10562

Middle Eastern (MID) AF: 0.466 AC: 136 AN: 292

European-Non Finnish (NFE) AF: 0.678 AC: 46007 AN: 67880

Other (OTH) AF: 0.566 AC: 1190 AN: 2102

Alfa AF: 0.406 Hom.: 941

Bravo AF: 0.530

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:1

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.57
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs397735050; hg19: chr1-55518190; COSMIC: COSV107390122;