Genetic Variant NM_174936.4:c.657+113_657+114delCC (chr1-55052517-ACC-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_174936.4(PCSK9):c.657+113_657+114delCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000415 in 1,444,174 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PCSK9
NM_174936.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.912

Publications

3 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.657+113_657+114delCC		intron_variant	Intron 4 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.657+107_657+108delCC		intron_variant	Intron 4 of 11	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151388

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000415

AC:

AN:

1444174

Hom.:

AF XY:

0.00000418

AC XY:

AN XY:

717130

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

32828

American (AMR)

AF:

0.00

AC:

AN:

43914

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25786

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39292

South Asian (SAS)

AF:

0.00

AC:

AN:

85250

European-Finnish (FIN)

AF:

0.0000389

AC:

AN:

51398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5574

European-Non Finnish (NFE)

AF:

0.00000273

AC:

AN:

1100502

Other (OTH)

AF:

0.00

AC:

AN:

59630

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.028390), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

151388

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73942

African (AFR)

AF:

0.00

AC:

AN:

40962

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5130

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67902

Other (OTH)

AF:

0.00

AC:

AN:

2082

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.91

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over