Variant 1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

BS2

High AC in GnomAd4 at 422 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.1503+68_1503+71dupGTGT		intron_variant		ENST00000302118.5	NP_777596.2	Q8NBP7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5 link	c.1503+19_1503+20insGTGT		intron_variant		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

Gnomad4 AFR exome

AF:

0.00143

Gnomad4 AMR exome

AF:

0.000860

Gnomad4 ASJ exome

AF:

0.000805

Gnomad4 EAS exome

AF:

0.000162

Gnomad4 SAS exome

AF:

0.00139

Gnomad4 FIN exome

AF:

0.00322

Gnomad4 NFE exome

AF:

0.000827

Gnomad4 OTH exome

AF:

0.000905

GnomAD4 genome

AF:

0.00296

AC:

422

AN:

142496

Hom.:

Cov.:

AF XY:

0.00291

AC XY:

201

AN XY:

69036

show subpopulations

Gnomad4 AFR

AF:

0.00425

Gnomad4 AMR

AF:

0.00110

Gnomad4 ASJ

AF:

0.000595

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000915

Gnomad4 FIN

AF:

0.00536

Gnomad4 NFE

AF:

0.00286

Gnomad4 OTH

AF:

0.00153

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

Benign, criteria provided, single submitter

clinical testing

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

Sep 30, 2019

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

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