Genetic Variant PCSK9:p.Leu21_Leu22dup (chr1-55039879-A-ACTGCTG) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_174936.4(PCSK9):c.60_65dupGCTGCT(p.Leu21_Leu22dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,557,940 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L22L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0033 ( 8 hom. )

Consequence

PCSK9
NM_174936.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: -0.246

Publications

14 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 -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_174936.4

BP6

Variant 1-55039879-A-ACTGCTG is Benign according to our data. Variant chr1-55039879-A-ACTGCTG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 265916.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00269 (409/152186) while in subpopulation AMR AF = 0.00366 (56/15300). AF 95% confidence interval is 0.00289. There are 1 homozygotes in GnomAd4. There are 190 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 8 AD,AR gene

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.60_65dupGCTGCT	p.Leu21_Leu22dup	disruptive_inframe_insertion	Exon 1 of 12	NP_777596.2
PCSK9	NM_001407240.1		c.60_65dupGCTGCT	p.Leu21_Leu22dup	disruptive_inframe_insertion	Exon 1 of 13	NP_001394169.1	A0AAQ5BGX4
PCSK9	NM_001407241.1		c.60_65dupGCTGCT	p.Leu21_Leu22dup	disruptive_inframe_insertion	Exon 1 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.60_65dupGCTGCT	p.Leu21_Leu22dup	disruptive_inframe_insertion	Exon 1 of 12	ENSP00000303208.5	Q8NBP7-1
PCSK9	ENST00000710286.1		c.417_422dupGCTGCT	p.Leu140_Leu141dup	disruptive_inframe_insertion	Exon 1 of 12	ENSP00000518176.1	A0AA34QVH0
PCSK9	ENST00000713786.1		c.60_65dupGCTGCT	p.Leu21_Leu22dup	disruptive_inframe_insertion	Exon 1 of 13	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes

AF:

0.00268

AC:

407

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000894

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.00366

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00311

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00325

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00277

AC:

446

AN:

161082

AF XY:

0.00272

show subpopulations

Gnomad AFR exome

AF:

0.000115

Gnomad AMR exome

AF:

0.00268

Gnomad ASJ exome

AF:

0.00734

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00401

Gnomad NFE exome

AF:

0.00329

Gnomad OTH exome

AF:

0.00557

GnomAD4 exome

AF:

0.00327

AC:

4595

AN:

1405754

Hom.:

Cov.:

AF XY:

0.00320

AC XY:

2220

AN XY:

694300

show subpopulations

African (AFR)

AF:

0.000622

AC:

AN:

32168

American (AMR)

AF:

0.00284

AC:

104

AN:

36632

Ashkenazi Jewish (ASJ)

AF:

0.00831

AC:

209

AN:

25156

East Asian (EAS)

AF:

0.0000542

AC:

AN:

36930

South Asian (SAS)

AF:

0.000902

AC:

AN:

79788

European-Finnish (FIN)

AF:

0.00405

AC:

198

AN:

48880

Middle Eastern (MID)

AF:

0.00358

AC:

AN:

4748

European-Non Finnish (NFE)

AF:

0.00347

AC:

3763

AN:

1083140

Other (OTH)

AF:

0.00360

AC:

210

AN:

58312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

315

630

944

1259

1574

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

146

292

438

584

730

<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:

0.00269

AC:

409

AN:

152186

Hom.:

Cov.:

AF XY:

0.00255

AC XY:

190

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.000963

AC:

AN:

41526

American (AMR)

AF:

0.00366

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000829

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00311

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00324

AC:

220

AN:

67988

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.00166

Hom.:

Bravo

AF:

0.00283

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypercholesterolemia, familial, 1 (4)

not provided (3)

not specified (3)

Cardiovascular phenotype (1)

Familial hypercholesterolemia (1)

Hypercholesterolemia, autosomal dominant, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.25

Mutation Taster

=81/19

polymorphism

(source)

Splicing

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

Publications

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1-55039879-ACTGCTGCTG-ACTGCTGCTGCTGCTG

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