Genetic Variant PCSK9:c.996+44A>T (chr1-55056233-A-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_174936.4(PCSK9):c.996+44A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.038 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0088 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

PCSK9
NM_174936.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.84

Publications

0 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
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 -14 ACMG points.

BP4

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

BP6

Variant 1-55056233-A-T is Benign according to our data. Variant chr1-55056233-A-T is described in ClinVar as Benign. ClinVar VariationId is 1711218.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174936.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PCSK9	NM_174936.4	MANE Select	c.996+44A>T	intron	N/A	NP_777596.2
PCSK9	NM_001407240.1		c.1119+44A>T	intron	N/A	NP_001394169.1	A0AAQ5BGX4
PCSK9	NM_001407241.1		c.996+44A>T	intron	N/A	NP_001394170.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.996+44A>T	intron	N/A	ENSP00000303208.5	Q8NBP7-1
PCSK9	ENST00000710286.1		c.1353+44A>T	intron	N/A	ENSP00000518176.1	A0AA34QVH0
PCSK9	ENST00000713786.1		c.1119+44A>T	intron	N/A	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes

AF:

0.0376

AC:

AN:

2474

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00193

Gnomad AMR

AF:

0.115

Gnomad ASJ

AF:

0.459

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.250

Gnomad NFE

AF:

0.289

Gnomad OTH

AF:

0.200

GnomAD2 exomes

AF:

0.000241

AC:

AN:

8282

AF XY:

0.000248

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00366

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00877

AC:

376

AN:

42874

Hom.:

Cov.:

AF XY:

0.00906

AC XY:

182

AN XY:

20088

show subpopulations

African (AFR)

AF:

0.00230

AC:

AN:

2172

American (AMR)

AF:

0.0484

AC:

AN:

124

Ashkenazi Jewish (ASJ)

AF:

0.257

AC:

146

AN:

568

East Asian (EAS)

AF:

0.00

AC:

AN:

424

South Asian (SAS)

AF:

0.00

AC:

AN:

1912

European-Finnish (FIN)

AF:

0.00

AC:

AN:

396

Middle Eastern (MID)

AF:

0.0574

AC:

AN:

122

European-Non Finnish (NFE)

AF:

0.00466

AC:

165

AN:

35438

Other (OTH)

AF:

0.0274

AC:

AN:

1718

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.672

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0376

AC:

AN:

2476

Hom.:

Cov.:

AF XY:

0.0325

AC XY:

AN XY:

1170

show subpopulations

African (AFR)

AF:

0.00192

AC:

AN:

2078

American (AMR)

AF:

0.112

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.459

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.250

AC:

AN:

European-Non Finnish (NFE)

AF:

0.289

AC:

AN:

128

Other (OTH)

AF:

0.200

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.20

(source)

DANN

Benign

0.32

PhyloP100

-1.8

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over