1-55057810-C-T

Variant names:

• chr1-55057810-C-T
• rs534347
• NM_174936.4:c.1181-226C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_174936.4(PCSK9):​c.1181-226C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.821 in 152,160 control chromosomes in the GnomAD database, including 51,464 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.82 (51464 hom., cov: 32)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0930
• 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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

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.1181-226C>T		intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.1304-226C>T		intron	N/A	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.1181-226C>T		intron	N/A	NP_001394170.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.1181-226C>T		intron	N/A	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.1538-226C>T		intron	N/A	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.1304-226C>T		intron	N/A	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.821 AC: 124786 AN: 152044 Hom.: 51430 Cov.: 32

Gnomad AFR AF: 0.755

Gnomad AMI AF: 0.874

Gnomad AMR AF: 0.876

Gnomad ASJ AF: 0.800

Gnomad EAS AF: 0.995

Gnomad SAS AF: 0.888

Gnomad FIN AF: 0.822

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.829

Gnomad OTH AF: 0.845

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.821 AC: 124873 AN: 152160 Hom.: 51464 Cov.: 32 AF XY: 0.823 AC XY: 61181 AN XY: 74384

African (AFR) AF: 0.755 AC: 31318 AN: 41478

American (AMR) AF: 0.876 AC: 13411 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.800 AC: 2778 AN: 3472

East Asian (EAS) AF: 0.995 AC: 5152 AN: 5176

South Asian (SAS) AF: 0.888 AC: 4280 AN: 4822

European-Finnish (FIN) AF: 0.822 AC: 8708 AN: 10598

Middle Eastern (MID) AF: 0.861 AC: 253 AN: 294

European-Non Finnish (NFE) AF: 0.829 AC: 56388 AN: 67992

Other (OTH) AF: 0.847 AC: 1788 AN: 2112

Alfa AF: 0.817 Hom.: 6610

Bravo AF: 0.822

Asia WGS AF: 0.921 AC: 3204 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.7
DANN	Benign	0.81
PhyloP100		0.093
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: rs534347; hg19: chr1-55523483;