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

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The ENST00000302118.5(PCSK9):c.1503+68_1503+71del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00558 in 1,379,622 control chromosomes in the GnomAD database, including 14 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 20 hom., cov: 0)

Exomes 𝑓: 0.0056 ( 14 hom. )

Failed GnomAD Quality Control

Consequence

PCSK9
ENST00000302118.5 intron

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 0.139

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-CGTGT-C is Benign according to our data. Variant chr1-55058666-CGTGT-C is described in ClinVar as [Likely_benign]. Clinvar id is 492239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55058666-CGTGT-C is described in Lovd as [Likely_benign]. Variant chr1-55058666-CGTGT-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00558 (7697/1379622) while in subpopulation AFR AF= 0.0154 (479/31118). AF 95% confidence interval is 0.0143. There are 14 homozygotes in gnomad4_exome. There are 3803 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

BS2

High AC in GnomAdExome4 at 7697 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4 linkuse as main transcript	c.1503+68_1503+71del		intron_variant		ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5 linkuse as main transcript	c.1503+68_1503+71del		intron_variant		1	NM_174936.4	ENSP00000303208	P2	Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

1661

AN:

142308

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0235

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.00833

Gnomad EAS

AF:

0.000421

Gnomad SAS

AF:

0.00206

Gnomad FIN

AF:

0.0316

Gnomad MID

AF:

0.00338

Gnomad NFE

AF:

0.00539

Gnomad OTH

AF:

0.00463

GnomAD3 exomes

AF:

0.00479

AC:

714

AN:

149146

Hom.:

AF XY:

0.00443

AC XY:

363

AN XY:

81986

show subpopulations

Gnomad AFR exome

AF:

0.0197

Gnomad AMR exome

AF:

0.00363

Gnomad ASJ exome

AF:

0.00608

Gnomad EAS exome

AF:

0.000270

Gnomad SAS exome

AF:

0.00192

Gnomad FIN exome

AF:

0.00754

Gnomad NFE exome

AF:

0.00433

Gnomad OTH exome

AF:

0.00519

GnomAD4 exome

AF:

0.00558

AC:

7697

AN:

1379622

Hom.:

AF XY:

0.00556

AC XY:

3803

AN XY:

684238

show subpopulations

Gnomad4 AFR exome

AF:

0.0154

Gnomad4 AMR exome

AF:

0.00389

Gnomad4 ASJ exome

AF:

0.00808

Gnomad4 EAS exome

AF:

0.00141

Gnomad4 SAS exome

AF:

0.00310

Gnomad4 FIN exome

AF:

0.0170

Gnomad4 NFE exome

AF:

0.00503

Gnomad4 OTH exome

AF:

0.00723

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0117

AC:

1663

AN:

142390

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

842

AN XY:

68976

show subpopulations

Gnomad4 AFR

AF:

0.0235

Gnomad4 AMR

AF:

0.00576

Gnomad4 ASJ

AF:

0.00833

Gnomad4 EAS

AF:

0.000422

Gnomad4 SAS

AF:

0.00229

Gnomad4 FIN

AF:

0.0316

Gnomad4 NFE

AF:

0.00539

Gnomad4 OTH

AF:

0.00460

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Hypercholesterolemia, familial, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 02, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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