Variant 1-55058443-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_174936.4(PCSK9):c.1355-56C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.833 in 1,610,942 control chromosomes in the GnomAD database, including 560,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.83 ( 52807 hom., cov: 32)

Exomes 𝑓: 0.83 ( 507368 hom. )

Consequence

PCSK9
NM_174936.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:2

Conservation

PhyloP100: -0.375

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 1-55058443-C-T is Benign according to our data. Variant chr1-55058443-C-T is described in ClinVar as [Benign]. Clinvar id is 265943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55058443-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4 linkuse as main transcript	c.1355-56C>T		intron_variant		ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5 linkuse as main transcript	c.1355-56C>T		intron_variant		1	NM_174936.4	P2	Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.832

AC:

126486

AN:

152036

Hom.:

52775

Cov.:

show subpopulations

Gnomad AFR

AF:

0.789

Gnomad AMI

AF:

0.874

Gnomad AMR

AF:

0.883

Gnomad ASJ

AF:

0.814

Gnomad EAS

AF:

0.991

Gnomad SAS

AF:

0.888

Gnomad FIN

AF:

0.822

Gnomad MID

AF:

0.863

Gnomad NFE

AF:

0.831

Gnomad OTH

AF:

0.856

GnomAD4 exome

AF:

0.833

AC:

1215572

AN:

1458790

Hom.:

507368

Cov.:

AF XY:

0.834

AC XY:

605618

AN XY:

725792

show subpopulations

Gnomad4 AFR exome

AF:

0.790

Gnomad4 AMR exome

AF:

0.911

Gnomad4 ASJ exome

AF:

0.813

Gnomad4 EAS exome

AF:

0.978

Gnomad4 SAS exome

AF:

0.874

Gnomad4 FIN exome

AF:

0.829

Gnomad4 NFE exome

AF:

0.824

Gnomad4 OTH exome

AF:

0.836

GnomAD4 genome

AF:

0.832

AC:

126572

AN:

152152

Hom.:

52807

Cov.:

AF XY:

0.834

AC XY:

62009

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.789

Gnomad4 AMR

AF:

0.883

Gnomad4 ASJ

AF:

0.814

Gnomad4 EAS

AF:

0.991

Gnomad4 SAS

AF:

0.888

Gnomad4 FIN

AF:

0.822

Gnomad4 NFE

AF:

0.831

Gnomad4 OTH

AF:

0.858

Alfa

AF:

0.797

Hom.:

3527

Bravo

AF:

0.834

Asia WGS

AF:

0.923

AC:

3211

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Short fetal femur length

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Phenosystems SA

- -

Hypercholesterolemia, familial, 1

Benign:1

Benign, criteria provided, single submitter

research

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Mar 01, 2016

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.6

DANN

Benign

0.74

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