Genetic Variant NM_174936.4:c.1503+50_1503+71delGTGTGTGTGTGTGTGTGTGTGT (chr1-55058666-CGTGTGTGTGTGTGTGTGTGTGT-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_174936.4(PCSK9):c.1503+50_1503+71delGTGTGTGTGTGTGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00085 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PCSK9
NM_174936.4 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.564

Publications

1 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
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 -8 ACMG points.

BP6

Variant 1-55058666-CGTGTGTGTGTGTGTGTGTGTGT-C is Benign according to our data. Variant chr1-55058666-CGTGTGTGTGTGTGTGTGTGTGT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 492233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.1503+50_1503+71delGTGTGTGTGTGTGTGTGTGTGT		intron_variant	Intron 9 of 11	ENST00000302118.5	NP_777596.2	Q8NBP7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5 link	c.1503+20_1503+41delGTGTGTGTGTGTGTGTGTGTGT		intron_variant	Intron 9 of 11	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.000597

AC:

AN:

142440

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000328

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00113

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000850

AC:

1184

AN:

1392822

Hom.:

AF XY:

0.000798

AC XY:

551

AN XY:

690614

show subpopulations

African (AFR)

AF:

0.000380

AC:

AN:

31608

American (AMR)

AF:

0.0000758

AC:

AN:

39552

Ashkenazi Jewish (ASJ)

AF:

0.000121

AC:

AN:

24878

East Asian (EAS)

AF:

0.00

AC:

AN:

36984

South Asian (SAS)

AF:

0.0000738

AC:

AN:

81354

European-Finnish (FIN)

AF:

0.000250

AC:

AN:

47984

Middle Eastern (MID)

AF:

0.000249

AC:

AN:

4014

European-Non Finnish (NFE)

AF:

0.00104

AC:

1114

AN:

1068890

Other (OTH)

AF:

0.000573

AC:

AN:

57558

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

100

149

199

249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

132

176

220

<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:

0.000597

AC:

AN:

142440

Hom.:

Cov.:

AF XY:

0.000566

AC XY:

AN XY:

68950

show subpopulations

African (AFR)

AF:

0.000159

AC:

AN:

37766

American (AMR)

AF:

0.000137

AC:

AN:

14588

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3364

East Asian (EAS)

AF:

0.00

AC:

AN:

4752

South Asian (SAS)

AF:

0.00

AC:

AN:

4378

European-Finnish (FIN)

AF:

0.000328

AC:

AN:

9152

Middle Eastern (MID)

AF:

0.00

AC:

AN:

296

European-Non Finnish (NFE)

AF:

0.00113

AC:

AN:

65320

Other (OTH)

AF:

0.00

AC:

AN:

1944

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

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:

0.00

Hom.:

1122

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3

Benign:1

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypercholesterolemia, familial, 1

Benign:1

Sep 05, 2017

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.56

Mutation Taster

=100/0

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over