1-55039879-ACTGCTGCTG-ACTGCTGCTGCTGCTG

Position:

chr1-55039879-ACTGCTGCTG-ACTGCTGCTGCTGCTG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_174936.4(PCSK9):c.60_65dup(p.Leu22_Leu23dup) variant causes a 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. P14P) 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 inframe_insertion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: -0.246

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

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 id is 265916.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1, Benign=5}.

BS2

High AC in GnomAd4 at 409 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4 linkuse as main transcript	c.60_65dup	p.Leu22_Leu23dup	inframe_insertion	1/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5 linkuse as main transcript	c.60_65dup	p.Leu22_Leu23dup	inframe_insertion	1/12	1	NM_174936.4	P2	Q8NBP7-1
PCSK9	ENST00000710286.1 linkuse as main transcript	c.417_422dup	p.Leu141_Leu142dup	inframe_insertion	1/12			A2
PCSK9	ENST00000673726.1 linkuse as main transcript	c.60_65dup	p.Leu22_Leu23dup	inframe_insertion, NMD_transcript_variant	1/6
PCSK9	ENST00000673913.2 linkuse as main transcript	c.60_65dup	p.Leu22_Leu23dup	inframe_insertion, NMD_transcript_variant	1/12

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

GnomAD3 exomes

AF:

0.00277

AC:

446

AN:

161082

Hom.:

AF XY:

0.00272

AC XY:

235

AN XY:

86248

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 SAS exome

AF:

0.000822

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

Gnomad4 AFR exome

AF:

0.000622

Gnomad4 AMR exome

AF:

0.00284

Gnomad4 ASJ exome

AF:

0.00831

Gnomad4 EAS exome

AF:

0.0000542

Gnomad4 SAS exome

AF:

0.000902

Gnomad4 FIN exome

AF:

0.00405

Gnomad4 NFE exome

AF:

0.00347

Gnomad4 OTH exome

AF:

0.00360

GnomAD4 genome

AF:

0.00269

AC:

409

AN:

152186

Hom.:

Cov.:

AF XY:

0.00255

AC XY:

190

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.000963

Gnomad4 AMR

AF:

0.00366

Gnomad4 ASJ

AF:

0.0101

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00311

Gnomad4 NFE

AF:

0.00324

Gnomad4 OTH

AF:

0.00427

Bravo

AF:

0.00283

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Uncertain:1Benign:3

Uncertain significance, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/100 French Canadian and 0/100 French normolipidemic and trigliceridemic controls; 0/100 Tunisian normolipidemic individuals -
Likely benign, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Jan 02, 2018	- -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 07, 2017	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 12, 2016	Variant summary: The PCSK9 c.60_65dupGCTGCT (p.Leu20_Leu21dup) variant involves the duplication of 6 nucleotides in a Leucine repeat region, changing 9 Leucines to 11 Leucines. Mutation taster predicts a benign outcome for this variant. This variant was found in 49/22348 control chromosomes (1 homozygote) at a frequency of 0.0021926, which is approximately 23 times the estimated maximal expected allele frequency of a pathogenic PCSK9 variant (0.0000938), suggesting this variant is likely a benign polymorphism. This variant has been reported in families with FH and FCHL but did not clearly cosegregate with disease. Additionally, the variant has been reported in patients that carry other pathogenic variants which would suggest that this is a benign variant. Taken together, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	PCSK9: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 28, 2020	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 05, 2021	The p.Leu22_Leu23dup variant in PCSK9 is classified as benign because it has been identified in 0.74% (65/8730) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hypercholesterolemia, autosomal dominant, 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 30, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial hypercholesterolemia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over