NM_174936.4:c.63_65delGCT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3BP6BS1

The NM_174936.4(PCSK9):c.63_65delGCT(p.Leu22del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000267 in 1,553,698 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L21L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

PCSK9
NM_174936.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:10

Conservation

PhyloP100: -0.0410

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: Likely_benign. The variant received -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_174936.4

BP6

Variant 1-55039879-ACTG-A is Benign according to our data. Variant chr1-55039879-ACTG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 265917.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000631 (96/152182) while in subpopulation AMR AF = 0.00307 (47/15300). AF 95% confidence interval is 0.00237. There are 0 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.63_65delGCT	p.Leu22del	disruptive_inframe_deletion	Exon 1 of 12	NP_777596.2
PCSK9	NM_001407240.1		c.63_65delGCT	p.Leu22del	disruptive_inframe_deletion	Exon 1 of 13	NP_001394169.1	A0AAQ5BGX4
PCSK9	NM_001407241.1		c.63_65delGCT	p.Leu22del	disruptive_inframe_deletion	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.63_65delGCT	p.Leu22del	disruptive_inframe_deletion	Exon 1 of 12	ENSP00000303208.5	Q8NBP7-1
PCSK9	ENST00000710286.1		c.420_422delGCT	p.Leu141del	disruptive_inframe_deletion	Exon 1 of 12	ENSP00000518176.1	A0AA34QVH0
PCSK9	ENST00000713786.1		c.63_65delGCT	p.Leu22del	disruptive_inframe_deletion	Exon 1 of 13	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes

AF:

0.000631

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000749

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000695

AC:

112

AN:

161082

AF XY:

0.000696

show subpopulations

Gnomad AFR exome

AF:

0.00162

Gnomad AMR exome

AF:

0.00138

Gnomad ASJ exome

AF:

0.000118

Gnomad EAS exome

AF:

0.000584

Gnomad FIN exome

AF:

0.000712

Gnomad NFE exome

AF:

0.000551

Gnomad OTH exome

AF:

0.00134

GnomAD4 exome

AF:

0.000228

AC:

319

AN:

1401516

Hom.:

AF XY:

0.000227

AC XY:

157

AN XY:

692260

show subpopulations

African (AFR)

AF:

0.000749

AC:

AN:

32058

American (AMR)

AF:

0.00151

AC:

AN:

36542

Ashkenazi Jewish (ASJ)

AF:

0.000319

AC:

AN:

25068

East Asian (EAS)

AF:

0.0000545

AC:

AN:

36730

South Asian (SAS)

AF:

0.00

AC:

AN:

79668

European-Finnish (FIN)

AF:

0.000391

AC:

AN:

48554

Middle Eastern (MID)

AF:

0.00211

AC:

AN:

4734

European-Non Finnish (NFE)

AF:

0.000149

AC:

161

AN:

1080024

Other (OTH)

AF:

0.000688

AC:

AN:

58138

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

118

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:

0.000631

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.000753

AC XY:

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

41526

American (AMR)

AF:

0.00307

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

67986

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.000707

Hom.:

Bravo

AF:

0.00115

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypercholesterolemia, familial, 1 (5)

not provided (2)

not specified (2)

Cardiovascular phenotype (1)

Hypercholesterolemia, autosomal dominant, 3 (1)

PCSK9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.041

Mutation Taster

=82/18

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