1-55061806-A-G

Variant names:

• chr1-55061806-A-G
• rs631220
• NM_174936.4:c.1863+250A>G

Variant summary

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

The NM_174936.4(PCSK9):​c.1863+250A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.824 in 152,232 control chromosomes in the GnomAD database, including 51,955 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 (51955 hom., cov: 33)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.353
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.968 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	NM_174936.4	MANE Select	c.1863+250A>G		intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.1986+250A>G		intron	N/A	NP_001394169.1
	PCSK9	NM_001407241.1		c.1905+250A>G		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.1863+250A>G		intron	N/A	ENSP00000303208.5
	PCSK9	ENST00000710286.1		c.2220+250A>G		intron	N/A	ENSP00000518176.1
	PCSK9	ENST00000713786.1		c.1986+250A>G		intron	N/A	ENSP00000519088.1

Frequencies

GnomAD3 genomes AF: 0.824 AC: 125413 AN: 152114 Hom.: 51924 Cov.: 33

Gnomad AFR AF: 0.763

Gnomad AMI AF: 0.876

Gnomad AMR AF: 0.880

Gnomad ASJ AF: 0.814

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.887

Gnomad FIN AF: 0.823

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.831

Gnomad OTH AF: 0.853

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

GnomAD4 genome AF: 0.824 AC: 125497 AN: 152232 Hom.: 51955 Cov.: 33 AF XY: 0.827 AC XY: 61526 AN XY: 74434

African (AFR) AF: 0.763 AC: 31686 AN: 41512

American (AMR) AF: 0.880 AC: 13478 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.814 AC: 2825 AN: 3472

East Asian (EAS) AF: 0.991 AC: 5132 AN: 5180

South Asian (SAS) AF: 0.886 AC: 4272 AN: 4820

European-Finnish (FIN) AF: 0.823 AC: 8727 AN: 10608

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

European-Non Finnish (NFE) AF: 0.831 AC: 56522 AN: 68016

Other (OTH) AF: 0.855 AC: 1805 AN: 2112

Alfa AF: 0.828 Hom.: 70078

Bravo AF: 0.826

Asia WGS AF: 0.919 AC: 3197 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.44
DANN	Benign	0.47
PhyloP100		-0.35
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: rs631220; hg19: chr1-55527479; COSMIC: COSV53764053; COSMIC: COSV53764053;