chr1-55058666-C-CGTGT

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_174936.4(PCSK9):c.1503+68_1503+71dupGTGT 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 0.0030 ( 2 hom., cov: 0)

Exomes 𝑓: 0.00094 ( 0 hom. )

Consequence

PCSK9
NM_174936.4 intron

Scores

Not classified

Clinical Significance

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

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: Benign. The variant received -16 ACMG points.

BP6

Variant 1-55058666-C-CGTGT is Benign according to our data. Variant chr1-55058666-C-CGTGT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 928567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00296 (422/142496) while in subpopulation AFR AF = 0.00425 (161/37860). AF 95% confidence interval is 0.00372. There are 2 homozygotes in GnomAd4. There are 201 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.1503+68_1503+71dupGTGT		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+20insGTGT		intron_variant	Intron 9 of 11	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.00296

AC:

421

AN:

142416

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00424

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00110

Gnomad ASJ

AF:

0.000595

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000914

Gnomad FIN

AF:

0.00536

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00286

Gnomad OTH

AF:

0.00154

GnomAD4 exome

AF:

0.000942

AC:

1310

AN:

1390592

Hom.:

Cov.:

AF XY:

0.000999

AC XY:

689

AN XY:

689450

show subpopulations

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

African (AFR)

AF:

0.00143

AC:

AN:

31562

American (AMR)

AF:

0.000860

AC:

AN:

39530

Ashkenazi Jewish (ASJ)

AF:

0.000805

AC:

AN:

24856

East Asian (EAS)

AF:

0.000162

AC:

AN:

36974

South Asian (SAS)

AF:

0.00139

AC:

113

AN:

81208

European-Finnish (FIN)

AF:

0.00322

AC:

154

AN:

47862

Middle Eastern (MID)

AF:

0.000747

AC:

AN:

4014

European-Non Finnish (NFE)

AF:

0.000827

AC:

883

AN:

1067124

Other (OTH)

AF:

0.000905

AC:

AN:

57462

⚠️ 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: 0.299

Heterozygous variant carriers

196

295

393

491

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:

0.00296

AC:

422

AN:

142496

Hom.:

Cov.:

AF XY:

0.00291

AC XY:

201

AN XY:

69036

show subpopulations

African (AFR)

AF:

0.00425

AC:

161

AN:

37860

American (AMR)

AF:

0.00110

AC:

AN:

14604

Ashkenazi Jewish (ASJ)

AF:

0.000595

AC:

AN:

3364

East Asian (EAS)

AF:

0.00

AC:

AN:

4740

South Asian (SAS)

AF:

0.000915

AC:

AN:

4372

European-Finnish (FIN)

AF:

0.00536

AC:

AN:

9146

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.00286

AC:

187

AN:

65302

Other (OTH)

AF:

0.00153

AC:

AN:

1956

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00311

Hom.:

1122

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Sep 30, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PCSK9 c.1503+68_1503+71dupGTGT is located at a highly polymorphic GT repeat region in intron and not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 149146 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1503+68_1503+71dupGTGT in individuals affected with Familial Hypercholesterolemia and no experimental evidence demonstrating its impact on protein function have been reported. One database lists this variant as benign (LOVD). Based on the evidence outlined above, the variant was classified as benign. -

Hypercholesterolemia, autosomal dominant, 3

Benign:1

Feb 02, 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

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