chr1-55061551-G-A

Position:

• chr1-55061551-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_174936.4(PCSK9):​c.1858G>A​(p.Glu620Lys) variant causes a missense 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24893677).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1858G>A	p.Glu620Lys	missense_variant	11/12	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.1858G>A	p.Glu620Lys	missense_variant	11/12	1	NM_174936.4	ENSP00000303208	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 29, 2016

This sequence change replaces glutamic acid with lysine at codon 620 of the PCSK9 protein (p.Glu620Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. While this variant is not present in population databases (ExAC no frequency), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in an individual with a PCSK9-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	0.0018	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.97	D;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.15
Sift	Benign	0.20	T
Sift4G	Benign	0.39	T
Polyphen		0.22	B
Vest4		0.34
MutPred		0.33		Gain of methylation at E620 (P = 0.0124);
MVP		0.82
MPC		0.30
ClinPred		0.45	T
GERP RS		1.8
Varity_R		0.19
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060500656; hg19: chr1-55527224;