NM_174936.4:c.1660C>G

Variant names:

• chr1-55059642-C-G
• rs149311926
• NM_174936.4:c.1660C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_174936.4(PCSK9):​c.1660C>G​(p.Gln554Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,551,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q554K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00083 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000087 (0 hom.)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: -0.0470
• Publications: 14 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054768324).
• BP6: Variant 1-55059642-C-G is Benign according to our data. Variant chr1-55059642-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 431558.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000834 (127/152302) while in subpopulation AFR AF = 0.00289 (120/41568). AF 95% confidence interval is 0.00247. There are 0 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.1660C>G	p.Gln554Glu	missense	Exon 10 of 12	NP_777596.2
	PCSK9	NM_001407240.1		c.1783C>G	p.Gln595Glu	missense	Exon 11 of 13	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.1702C>G	p.Gln568Glu	missense	Exon 10 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.1660C>G	p.Gln554Glu	missense	Exon 10 of 12	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.2017C>G	p.Gln673Glu	missense	Exon 10 of 12	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.1783C>G	p.Gln595Glu	missense	Exon 11 of 13	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.000835 AC: 127 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000179 AC: 28 AN: 156836 AF XY: 0.0000968

Gnomad AFR exome AF: 0.00251

Gnomad AMR exome AF: 0.000161

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000329

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000872 AC: 122 AN: 1398906 Hom.: 0 Cov.: 32 AF XY: 0.0000725 AC XY: 50 AN XY: 690016

African (AFR) AF: 0.00344 AC: 109 AN: 31648

American (AMR) AF: 0.000112 AC: 4 AN: 35732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35840

South Asian (SAS) AF: 0.00 AC: 0 AN: 79226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5164

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1079146

Other (OTH) AF: 0.000103 AC: 6 AN: 57972

GnomAD4 genome AF: 0.000834 AC: 127 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.000712 AC XY: 53 AN XY: 74478

African (AFR) AF: 0.00289 AC: 120 AN: 41568

American (AMR) AF: 0.000261 AC: 4 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.0000638 Hom.: 0

Bravo AF: 0.00103

ESP6500AA AF: 0.00212 AC: 9

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000132 AC: 12

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Hypercholesterolemia, autosomal dominant, 3 (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Familial hypercholesterolemia (1)
-	1	-	Hypercholesterolemia, familial, 1 (1)
-	1	-	Hypobetalipoproteinemia (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	3.5
DANN	Benign	0.43
DEOGEN2	Benign	0.064	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.91	L
PhyloP100		-0.047
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.086
Sift	Benign	0.75	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.14
MVP		0.59
MPC		0.24
ClinPred		0.010	T
GERP RS		0.034
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.48
Mutation Taster		=89/11	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: rs149311926; hg19: chr1-55525315;