Genetic Variant PCSK9:p.Pro331Pro (chr1-55056186-C-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_StrongBP6_Very_StrongBP7BS1BS2_Supporting

The NM_174936.4(PCSK9):c.993C>T(p.Pro331Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000294 in 1,457,672 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P331P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00029 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 2 hom. )

Consequence

PCSK9
NM_174936.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -3.07

Publications

2 publications found

Variant links:

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

PCSK9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 1-55056186-C-T is Benign according to our data. Variant chr1-55056186-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 496568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.07 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000287 (43/149774) while in subpopulation EAS AF = 0.00322 (16/4964). AF 95% confidence interval is 0.00202. There are 1 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCSK9	NM_174936.4	MANE Select	c.993C>T	p.Pro331Pro	synonymous	Exon 6 of 12	NP_777596.2
PCSK9	NM_001407240.1		c.1116C>T	p.Pro372Pro	synonymous	Exon 7 of 13	NP_001394169.1	A0AAQ5BGX4
PCSK9	NM_001407241.1		c.993C>T	p.Pro331Pro	synonymous	Exon 6 of 12	NP_001394170.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.993C>T	p.Pro331Pro	synonymous	Exon 6 of 12	ENSP00000303208.5	Q8NBP7-1
PCSK9	ENST00000710286.1		c.1350C>T	p.Pro450Pro	synonymous	Exon 6 of 12	ENSP00000518176.1	A0AA34QVH0
PCSK9	ENST00000713786.1		c.1116C>T	p.Pro372Pro	synonymous	Exon 7 of 13	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes

AF:

0.000287

AC:

AN:

149658

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000248

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000201

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00322

Gnomad SAS

AF:

0.00147

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000148

Gnomad OTH

AF:

0.000488

GnomAD2 exomes

AF:

0.000597

AC:

AN:

120672

AF XY:

0.000635

show subpopulations

Gnomad AFR exome

AF:

0.000140

Gnomad AMR exome

AF:

0.000158

Gnomad ASJ exome

AF:

0.00197

Gnomad EAS exome

AF:

0.00351

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000203

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.000294

AC:

385

AN:

1307898

Hom.:

Cov.:

AF XY:

0.000297

AC XY:

189

AN XY:

636958

show subpopulations

African (AFR)

AF:

0.0000337

AC:

AN:

29716

American (AMR)

AF:

0.0000623

AC:

AN:

32110

Ashkenazi Jewish (ASJ)

AF:

0.00201

AC:

AN:

20924

East Asian (EAS)

AF:

0.00464

AC:

157

AN:

33824

South Asian (SAS)

AF:

0.000610

AC:

AN:

65592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44340

Middle Eastern (MID)

AF:

0.000505

AC:

AN:

3962

European-Non Finnish (NFE)

AF:

0.000103

AC:

105

AN:

1024238

Other (OTH)

AF:

0.000677

AC:

AN:

53192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000287

AC:

AN:

149774

Hom.:

Cov.:

AF XY:

0.000315

AC XY:

AN XY:

73032

show subpopulations

African (AFR)

AF:

0.0000247

AC:

AN:

40486

American (AMR)

AF:

0.000201

AC:

AN:

14954

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3468

East Asian (EAS)

AF:

0.00322

AC:

AN:

4964

South Asian (SAS)

AF:

0.00147

AC:

AN:

4754

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10196

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.000148

AC:

AN:

67684

Other (OTH)

AF:

0.000483

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000619

Hom.:

Bravo

AF:

0.000404

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Cardiovascular phenotype (1)

Familial hypercholesterolemia (1)

Hypercholesterolemia, autosomal dominant, 3 (1)

Hypercholesterolemia, familial, 1 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

7.0

(source)

DANN

Benign

0.87

PhyloP100

-3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over