1-55052493-G-A

Variant names:

• chr1-55052493-G-A
• rs625619
• NM_174936.4:c.657+82G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_174936.4(PCSK9):​c.657+82G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 1,607,646 control chromosomes in the GnomAD database, including 262,931 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (21035 hom., cov: 33)
  • Exomes 𝑓: 0.57 (241896 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.169
• Publications: 12 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-55052493-G-A is Benign according to our data. Variant chr1-55052493-G-A is described in ClinVar as Benign. ClinVar VariationId is 265925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.761 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	NM_174936.4	MANE Select	c.657+82G>A		intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.780+82G>A		intron	N/A	NP_001394169.1
	PCSK9	NM_001407241.1		c.657+82G>A		intron	N/A	NP_001394170.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.657+82G>A		intron	N/A	ENSP00000303208.5
	PCSK9	ENST00000710286.1		c.1014+82G>A		intron	N/A	ENSP00000518176.1
	PCSK9	ENST00000713786.1		c.780+82G>A		intron	N/A	ENSP00000519088.1

Frequencies

GnomAD3 genomes AF: 0.508 AC: 76899 AN: 151350 Hom.: 21027 Cov.: 33

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.602

Gnomad AMR AF: 0.655

Gnomad ASJ AF: 0.502

Gnomad EAS AF: 0.781

Gnomad SAS AF: 0.538

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.558

GnomAD4 exome AF: 0.573 AC: 833684 AN: 1456178 Hom.: 241896 Cov.: 38 AF XY: 0.571 AC XY: 413172 AN XY: 723892

African (AFR) AF: 0.292 AC: 9755 AN: 33394

American (AMR) AF: 0.692 AC: 30743 AN: 44398

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 12909 AN: 26082

East Asian (EAS) AF: 0.763 AC: 30183 AN: 39578

South Asian (SAS) AF: 0.525 AC: 45105 AN: 85886

European-Finnish (FIN) AF: 0.481 AC: 24966 AN: 51864

Middle Eastern (MID) AF: 0.471 AC: 2683 AN: 5692

European-Non Finnish (NFE) AF: 0.580 AC: 643213 AN: 1109080

Other (OTH) AF: 0.567 AC: 34127 AN: 60204

GnomAD4 genome AF: 0.508 AC: 76941 AN: 151468 Hom.: 21035 Cov.: 33 AF XY: 0.507 AC XY: 37505 AN XY: 73954

African (AFR) AF: 0.301 AC: 12470 AN: 41460

American (AMR) AF: 0.655 AC: 9987 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.502 AC: 1740 AN: 3468

East Asian (EAS) AF: 0.782 AC: 4017 AN: 5140

South Asian (SAS) AF: 0.538 AC: 2571 AN: 4782

European-Finnish (FIN) AF: 0.470 AC: 4880 AN: 10372

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.583 AC: 39439 AN: 67706

Other (OTH) AF: 0.559 AC: 1171 AN: 2096

Alfa AF: 0.485 Hom.: 3873

Bravo AF: 0.514

Asia WGS AF: 0.630 AC: 2190 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:1

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.6
DANN	Benign	0.55
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism (auto)

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: rs625619; hg19: chr1-55518166;