dbSNP rs778796405: PCSK9:p.Arg9Arg (chr1-55039507-C-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP7

The ENST00000710286.1(PCSK9):c.27C>A(p.Arg9Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 443,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

PCSK9
ENST00000710286.1 synonymous

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: -1.65

Publications

3 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP7

Synonymous conserved (PhyloP=-1.65 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000710286.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PCSK9	NM_174936.4	MANE Select	c.-331C>A	upstream_gene	N/A	NP_777596.2
PCSK9	NM_001407240.1		c.-331C>A	upstream_gene	N/A	NP_001394169.1	A0AAQ5BGX4
PCSK9	NM_001407241.1		c.-331C>A	upstream_gene	N/A	NP_001394170.1

Ensembl Transcripts

Gene	Transcript	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCSK9	ENST00000710286.1	c.27C>A	p.Arg9Arg	synonymous	Exon 1 of 12	ENSP00000518176.1	A0AA34QVH0
PCSK9	ENST00000713786.1	c.-331C>A		5_prime_UTR	Exon 1 of 13	ENSP00000519088.1	A0AAQ5BGX4
PCSK9	ENST00000673726.2	n.-331C>A		non_coding_transcript_exon	Exon 1 of 13	ENSP00000501004.1	A0A669KAY4

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000251

AC:

AN:

290704

Hom.:

Cov.:

AF XY:

0.000192

AC XY:

AN XY:

150678

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

7504

American (AMR)

AF:

0.00

AC:

AN:

11052

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9134

East Asian (EAS)

AF:

0.00

AC:

AN:

18346

South Asian (SAS)

AF:

0.000135

AC:

AN:

29636

European-Finnish (FIN)

AF:

0.0000534

AC:

AN:

18726

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1332

European-Non Finnish (NFE)

AF:

0.000378

AC:

AN:

177394

Other (OTH)

AF:

0.0000569

AC:

AN:

17580

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

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:

0.000243

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41590

American (AMR)

AF:

0.000261

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000441

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2110

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

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:

0.000569

Hom.:

Bravo

AF:

0.000268

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypercholesterolemia, autosomal dominant, 3 (3)

Hypercholesterolemia, familial, 1 (1)

Hypobetalipoproteinemia (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

5.1

(source)

DANN

Benign

0.90

PhyloP100

-1.7

PromoterAI

0.0016

Neutral

(source)

Splicing

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