chr1-55052518-C-T

Variant names:

• chr1-55052518-C-T
• rs886039846
• NM_174936.4:c.657+107C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000302118.5(PCSK9):​c.657+107C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: PCSK9 ENST00000302118.5 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.574
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000302118.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	NM_174936.4	MANE Select	c.657+107C>T		intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.780+107C>T		intron	N/A	NP_001394169.1
	PCSK9	NM_001407241.1		c.657+107C>T		intron	N/A	NP_001394170.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.657+107C>T		intron	N/A	ENSP00000303208.5
	PCSK9	ENST00000710286.1		c.1014+107C>T		intron	N/A	ENSP00000518176.1
	PCSK9	ENST00000713786.1		c.780+107C>T		intron	N/A	ENSP00000519088.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.0000314 AC: 5 AN: 159326 Hom.: 0 Cov.: 0 AF XY: 0.0000250 AC XY: 2 AN XY: 80012

African (AFR) AF: 0.00 AC: 0 AN: 20220

American (AMR) AF: 0.00 AC: 0 AN: 3686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4726

East Asian (EAS) AF: 0.00 AC: 0 AN: 2666

South Asian (SAS) AF: 0.00 AC: 0 AN: 14796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1216

European-Non Finnish (NFE) AF: 0.0000394 AC: 4 AN: 101456

Other (OTH) AF: 0.000132 AC: 1 AN: 7548

GnomAD4 genome Cov.: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hypercholesterolemia, familial, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.2
DANN	Benign	0.42
PhyloP100		-0.57

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: rs886039846; hg19: chr1-55518191;