rs886046429

Variant names:

• chr1-55039638-C-A
• rs886046429
• NM_174936.4:c.-200C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-55039638-C-A
• chr1-55039638-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_174936.4(PCSK9):​c.-200C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCSK9 NM_174936.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.234
• Publications: 0 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174936.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	NM_174936.4	MANE Select	c.-200C>A		5_prime_UTR	Exon 1 of 12	NP_777596.2
	PCSK9	NM_001407240.1		c.-200C>A		5_prime_UTR	Exon 1 of 13	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.-200C>A		5_prime_UTR	Exon 1 of 12	NP_001394170.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.-200C>A		5_prime_UTR	Exon 1 of 12	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.158C>A	p.Ala53Asp	missense	Exon 1 of 12	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.-200C>A		5_prime_UTR	Exon 1 of 13	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 499760 Hom.: 0 Cov.: 6 AF XY: 0.00 AC XY: 0 AN XY: 260946

African (AFR) AF: 0.00 AC: 0 AN: 13394

American (AMR) AF: 0.00 AC: 0 AN: 20304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14134

East Asian (EAS) AF: 0.00 AC: 0 AN: 31126

South Asian (SAS) AF: 0.00 AC: 0 AN: 47236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2062

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 313854

Other (OTH) AF: 0.00 AC: 0 AN: 27610

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.4
DANN	Benign	0.63
PhyloP100		0.23
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Mutation Taster		=293/7	polymorphism

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: rs886046429; hg19: chr1-55505311;