1-55056240-A-G

Variant names:

• chr1-55056240-A-G
• rs45573036
• NM_174936.4:c.996+51A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_174936.4(PCSK9):​c.996+51A>G 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.330
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.996+51A>G		intron_variant	Intron 6 of 11	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.996+51A>G		intron_variant	Intron 6 of 11	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.000333 AC: 1 AN: 3002 Hom.: 0 Cov.: 0

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: 0.000698

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000946 AC: 3 AN: 31718 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 15978

African (AFR) AF: 0.00 AC: 0 AN: 800

American (AMR) AF: 0.00 AC: 0 AN: 464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 756

East Asian (EAS) AF: 0.000430 AC: 1 AN: 2326

South Asian (SAS) AF: 0.00 AC: 0 AN: 476

European-Finnish (FIN) AF: 0.000195 AC: 1 AN: 5130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 92

European-Non Finnish (NFE) AF: 0.0000497 AC: 1 AN: 20114

Other (OTH) AF: 0.00 AC: 0 AN: 1560

GnomAD4 genome AF: 0.000333 AC: 1 AN: 3002 Hom.: 0 Cov.: 0 AF XY: 0.000599 AC XY: 1 AN XY: 1670

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

African (AFR) AF: 0.00 AC: 0 AN: 770

American (AMR) AF: 0.00 AC: 0 AN: 264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 90

East Asian (EAS) AF: 0.00 AC: 0 AN: 138

South Asian (SAS) AF: 0.00 AC: 0 AN: 110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 18

European-Non Finnish (NFE) AF: 0.000698 AC: 1 AN: 1432

Other (OTH) AF: 0.00 AC: 0 AN: 54

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0113 Hom.: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:1

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.9
DANN	Benign	0.32
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs45573036; hg19: chr1-55521913;