Genetic Variant NM_174936.4:c.1503+66_1503+71dupGTGTGT (chr1-55058666-C-CGTGTGT) – 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+66_1503+71dupGTGTGT 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 0.0015 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00065 ( 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-CGTGTGT is Benign according to our data. Variant chr1-55058666-C-CGTGTGT is described in ClinVar as Likely_benign. ClinVar VariationId is 1660177.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+66_1503+71dupGTGTGT		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+20insGTGTGT		intron_variant	Intron 9 of 11	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.00154

AC:

220

AN:

142424

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000636

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000411

Gnomad ASJ

AF:

0.00297

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000228

Gnomad FIN

AF:

0.00394

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00217

Gnomad OTH

AF:

0.000514

GnomAD4 exome

AF:

0.000649

AC:

904

AN:

1391992

Hom.:

Cov.:

AF XY:

0.000684

AC XY:

472

AN XY:

690208

show subpopulations

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

African (AFR)

AF:

0.000285

AC:

AN:

31616

American (AMR)

AF:

0.000228

AC:

AN:

39544

Ashkenazi Jewish (ASJ)

AF:

0.00121

AC:

AN:

24868

East Asian (EAS)

AF:

0.0000270

AC:

AN:

36988

South Asian (SAS)

AF:

0.000664

AC:

AN:

81324

European-Finnish (FIN)

AF:

0.00186

AC:

AN:

47940

Middle Eastern (MID)

AF:

0.000498

AC:

AN:

4014

European-Non Finnish (NFE)

AF:

0.000631

AC:

674

AN:

1068182

Other (OTH)

AF:

0.000626

AC:

AN:

57516

⚠️ 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: 0.311

Heterozygous variant carriers

123

185

246

308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.00154

AC:

220

AN:

142504

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

112

AN XY:

69040

show subpopulations

African (AFR)

AF:

0.000634

AC:

AN:

37866

American (AMR)

AF:

0.000411

AC:

AN:

14604

Ashkenazi Jewish (ASJ)

AF:

0.00297

AC:

AN:

3364

East Asian (EAS)

AF:

0.00

AC:

AN:

4740

South Asian (SAS)

AF:

0.000229

AC:

AN:

4372

European-Finnish (FIN)

AF:

0.00394

AC:

AN:

9140

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.00217

AC:

142

AN:

65308

Other (OTH)

AF:

0.000511

AC:

AN:

1958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

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

Oct 22, 2024

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

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