rs7552471

Positions:

• chr1-55052697-C-A
• chr1-55052697-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_174936.4(PCSK9):​c.705C>A​(p.Ser235Arg) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S235S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 35)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4	c.705C>A	p.Ser235Arg	missense_variant	5/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5	c.705C>A	p.Ser235Arg	missense_variant	5/12	1	NM_174936.4	P2

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 82

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.68	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.59
Sift	Benign	0.044	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.72		Gain of methylation at S235 (P = 0.0082);
MVP		0.84
MPC		0.89
ClinPred		0.98	D
GERP RS		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.91
gMVP		0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs7552471; hg19: chr1-55518370;