chr1-55052400-T-C

Variant names:

• chr1-55052400-T-C
• rs28942112
• NM_174936.4:c.646T>C
• PCSK9 p.Phe216Leu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+5 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 5 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PP5

The NM_174936.4(PCSK9):c.646T>C (p.Phe216Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (no review stars). This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Hypercholesterolemia, autosomal dominant, 3 (hchola3).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 5.27
• Publications: 46 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), Ambry Genetics, Genomics England PanelApp
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 5 pathogenic, 0 benign (OR vs. background: 55.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.000137 by highest known P/LP ClinVar AF 0.000137) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar 0-star pathogenic — supporting (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 0 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_174936.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PCSK9 NM_174936.4	MANE Select	c.646T>C p.Phe216Leu	missense	Exon 4 of 12	Prot: NP_777596.2
	PCSK9 NM_001407240.1		c.769T>C p.Phe257Leu	missense	Exon 5 of 13	Prot: NP_001394169.1 UniProt:
	PCSK9 NM_001407241.1		c.646T>C p.Phe216Leu	missense	Exon 4 of 12	Prot: NP_001394170.1

PCSK9 NM_174936.4

MANE Select

HGVSc / HGVSpc.646T>Cp.Phe216Leu

Exon rankExon 4 of 12

missense

Prot: NP_777596.2

PCSK9 NM_001407240.1

HGVSc / HGVSpc.769T>Cp.Phe257Leu

Exon rankExon 5 of 13

missense

Prot: NP_001394169.1UniProt: A0AAQ5BGX4

PCSK9 NM_001407241.1

HGVSc / HGVSpc.646T>Cp.Phe216Leu

Exon rankExon 4 of 12

missense

Prot: NP_001394170.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PCSK9 ENST00000302118.5	TSL:1MANE Select	c.646T>C p.Phe216Leu	missense	Exon 4 of 12	Prot: ENSP00000303208.5 UniProt:
	PCSK9 ENST00000710286.1		c.1003T>C p.Phe335Leu	missense	Exon 4 of 12	Prot: ENSP00000518176.1 UniProt:
	PCSK9 ENST00000713786.1		c.769T>C p.Phe257Leu	missense	Exon 5 of 13	Prot: ENSP00000519088.1 UniProt:

PCSK9 ENST00000302118.5

TSL:1MANE Select

HGVSc / HGVSpc.646T>Cp.Phe216Leu

Exon rankExon 4 of 12

missense

Prot: ENSP00000303208.5UniProt: Q8NBP7-1

PCSK9 ENST00000710286.1

HGVSc / HGVSpc.1003T>Cp.Phe335Leu

Exon rankExon 4 of 12

missense

Prot: ENSP00000518176.1UniProt: A0AA34QVH0

PCSK9 ENST00000713786.1

HGVSc / HGVSpc.769T>Cp.Phe257Leu

Exon rankExon 5 of 13

missense

Prot: ENSP00000519088.1UniProt: A0AAQ5BGX4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:35
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000247	AC:1	Hom:0	AN:40510	Cov:

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hypercholesterolemia, autosomal dominant, 3 (2)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.091
Eigen_PC	Benign	0.098
FATHMM_MKL	Uncertain	0.95	D
FuncVEP CTI	Pathogenic	0.68
GPN-Star LLR	N/A	-6.6
GPN-Star score	N/A	6.6
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	-0.15	T
Mutation Taster	N/A	22/78	disease causing (ClinVar)
MutationAssessor	Benign	1.3	L
PhyloP100	Uncertain	5.3
popEVE	Benign	-3.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.7	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.8
REVEL	Uncertain	0.60
Sift	Benign	0.075	T
Sift4G	Uncertain	0.039	D
Varity_R	N/A	0.41
VESM-3B	Benign	-6.1

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs28942112;

hg19: chr1-55518073;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar