Genetic Variant NM_174936.4:c.1503+64_1503+71dupGTGTGTGT (chr1-55058666-C-CGTGTGTGT) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_174936.4(PCSK9):c.1503+64_1503+71dupGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 0)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

PCSK9
NM_174936.4 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.20

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: Likely_benign. The variant received -2 ACMG points.

BP6

Variant 1-55058666-C-CGTGTGTGT is Benign according to our data. Variant chr1-55058666-C-CGTGTGTGT is described in ClinVar as Likely_benign. ClinVar VariationId is 1621636.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.1503+64_1503+71dupGTGTGTGT		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+19_1503+20insGTGTGTGT		intron_variant	Intron 9 of 11	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.00119

AC:

169

AN:

142430

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000715

Gnomad AMI

AF:

0.00227

Gnomad AMR

AF:

0.000823

Gnomad ASJ

AF:

0.00208

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00114

Gnomad FIN

AF:

0.000546

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00168

Gnomad OTH

AF:

0.000514

GnomAD4 exome

AF:

0.000345

AC:

481

AN:

1392412

Hom.:

Cov.:

AF XY:

0.000343

AC XY:

237

AN XY:

690438

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000158

AC:

AN:

31620

American (AMR)

AF:

0.000379

AC:

AN:

39544

Ashkenazi Jewish (ASJ)

AF:

0.000322

AC:

AN:

24878

East Asian (EAS)

AF:

0.00

AC:

AN:

36988

South Asian (SAS)

AF:

0.0000983

AC:

AN:

81352

European-Finnish (FIN)

AF:

0.000354

AC:

AN:

47974

Middle Eastern (MID)

AF:

0.000249

AC:

AN:

4014

European-Non Finnish (NFE)

AF:

0.000379

AC:

405

AN:

1068498

Other (OTH)

AF:

0.000382

AC:

AN:

57544

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.320

Heterozygous variant carriers

127

159

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:

0.00118

AC:

168

AN:

142510

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

AN XY:

69042

show subpopulations

African (AFR)

AF:

0.000713

AC:

AN:

37866

American (AMR)

AF:

0.000822

AC:

AN:

14602

Ashkenazi Jewish (ASJ)

AF:

0.00208

AC:

AN:

3364

East Asian (EAS)

AF:

0.00

AC:

AN:

4740

South Asian (SAS)

AF:

0.000915

AC:

AN:

4370

European-Finnish (FIN)

AF:

0.000546

AC:

AN:

9152

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.00168

AC:

110

AN:

65306

Other (OTH)

AF:

0.000511

AC:

AN:

1958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

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:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3

Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

-1.2

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