rs2495482

Variant names:

• chr1-55040059-A-G
• rs2495482
• NM_174936.4:c.207+15A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-55040059-A-G
• chr1-55040059-A-T

Variant summary

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

The NM_001407246.1(PCSK9):​c.-513A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.944 in 1,553,126 control chromosomes in the GnomAD database, including 692,792 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.92 (64013 hom., cov: 38)
  • Exomes 𝑓: 0.95 (628779 hom.)
• Consequence: PCSK9 NM_001407246.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.224
• Publications: 14 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=-0.85).
• BP6: Variant 1-55040059-A-G is Benign according to our data. Variant chr1-55040059-A-G is described in ClinVar as Benign. ClinVar VariationId is 262904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.95 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407246.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	NM_174936.4	MANE Select	c.207+15A>G		intron	N/A	NP_777596.2
	PCSK9	NM_001407246.1		c.-513A>G		5_prime_UTR	Exon 1 of 12	NP_001394175.1
	PCSK9	NM_001407240.1		c.207+15A>G		intron	N/A	NP_001394169.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.207+15A>G		intron	N/A	ENSP00000303208.5
	PCSK9	ENST00000710286.1		c.564+15A>G		intron	N/A	ENSP00000518176.1
	PCSK9	ENST00000713786.1		c.207+15A>G		intron	N/A	ENSP00000519088.1

Frequencies

GnomAD3 genomes AF: 0.915 AC: 139342 AN: 152240 Hom.: 63976 Cov.: 38

Gnomad AFR AF: 0.835

Gnomad AMI AF: 0.952

Gnomad AMR AF: 0.903

Gnomad ASJ AF: 0.929

Gnomad EAS AF: 0.943

Gnomad SAS AF: 0.973

Gnomad FIN AF: 0.969

Gnomad MID AF: 0.920

Gnomad NFE AF: 0.951

Gnomad OTH AF: 0.921

GnomAD2 exomes AF: 0.928 AC: 147203 AN: 158652 AF XY: 0.936

Gnomad AFR exome AF: 0.830

Gnomad AMR exome AF: 0.836

Gnomad ASJ exome AF: 0.928

Gnomad EAS exome AF: 0.941

Gnomad FIN exome AF: 0.965

Gnomad NFE exome AF: 0.951

Gnomad OTH exome AF: 0.942

GnomAD4 exome AF: 0.947 AC: 1326590 AN: 1400768 Hom.: 628779 Cov.: 65 AF XY: 0.949 AC XY: 655717 AN XY: 691306

African (AFR) AF: 0.824 AC: 26196 AN: 31786

American (AMR) AF: 0.844 AC: 30671 AN: 36360

Ashkenazi Jewish (ASJ) AF: 0.929 AC: 23392 AN: 25188

East Asian (EAS) AF: 0.957 AC: 34475 AN: 36038

South Asian (SAS) AF: 0.970 AC: 76973 AN: 79368

European-Finnish (FIN) AF: 0.965 AC: 47003 AN: 48726

Middle Eastern (MID) AF: 0.943 AC: 4046 AN: 4292

European-Non Finnish (NFE) AF: 0.952 AC: 1029220 AN: 1080988

Other (OTH) AF: 0.941 AC: 54614 AN: 58022

GnomAD4 genome AF: 0.915 AC: 139434 AN: 152358 Hom.: 64013 Cov.: 38 AF XY: 0.917 AC XY: 68323 AN XY: 74510

African (AFR) AF: 0.835 AC: 34714 AN: 41572

American (AMR) AF: 0.902 AC: 13815 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.929 AC: 3224 AN: 3472

East Asian (EAS) AF: 0.943 AC: 4889 AN: 5182

South Asian (SAS) AF: 0.973 AC: 4705 AN: 4834

European-Finnish (FIN) AF: 0.969 AC: 10306 AN: 10632

Middle Eastern (MID) AF: 0.918 AC: 268 AN: 292

European-Non Finnish (NFE) AF: 0.951 AC: 64698 AN: 68038

Other (OTH) AF: 0.921 AC: 1947 AN: 2114

Alfa AF: 0.911 Hom.: 23111

Bravo AF: 0.904

Asia WGS AF: 0.953 AC: 3315 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hypercholesterolemia, autosomal dominant, 3 (4)
-	-	4	not specified (4)
-	-	3	Hypercholesterolemia, familial, 1 (3)
-	-	2	Familial hypercholesterolemia (2)
-	-	2	not provided (2)
-	-	1	Hypobetalipoproteinemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.8
DANN	Benign	0.46
PhyloP100		0.22
PromoterAI		0.12	Neutral
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		1.9
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: rs2495482; hg19: chr1-55505732;