rs585131

Variant names:

• chr1-55058443-C-T
• rs585131
• NM_174936.4:c.1355-56C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-55058443-C-T
• chr1-55058443-C-A
• chr1-55058443-C-G

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.1355-56C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.833 in 1,610,942 control chromosomes in the GnomAD database, including 560,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (52807 hom., cov: 32)
  • Exomes 𝑓: 0.83 (507368 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:2
• Conservation: PhyloP100: -0.375
• Publications: 20 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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=-0.88).
• BP6: Variant 1-55058443-C-T is Benign according to our data. Variant chr1-55058443-C-T is described in ClinVar as Benign. ClinVar VariationId is 265943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.968 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	NM_174936.4	MANE Select	c.1355-56C>T		intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.1478-56C>T		intron	N/A	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.1355-56C>T		intron	N/A	NP_001394170.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.1355-56C>T		intron	N/A	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.1712-56C>T		intron	N/A	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.1478-56C>T		intron	N/A	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.832 AC: 126486 AN: 152036 Hom.: 52775 Cov.: 32

Gnomad AFR AF: 0.789

Gnomad AMI AF: 0.874

Gnomad AMR AF: 0.883

Gnomad ASJ AF: 0.814

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.888

Gnomad FIN AF: 0.822

Gnomad MID AF: 0.863

Gnomad NFE AF: 0.831

Gnomad OTH AF: 0.856

GnomAD4 exome AF: 0.833 AC: 1215572 AN: 1458790 Hom.: 507368 Cov.: 50 AF XY: 0.834 AC XY: 605618 AN XY: 725792

African (AFR) AF: 0.790 AC: 26359 AN: 33372

American (AMR) AF: 0.911 AC: 40733 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.813 AC: 21244 AN: 26130

East Asian (EAS) AF: 0.978 AC: 38842 AN: 39696

South Asian (SAS) AF: 0.874 AC: 75233 AN: 86124

European-Finnish (FIN) AF: 0.829 AC: 44227 AN: 53368

Middle Eastern (MID) AF: 0.873 AC: 3616 AN: 4144

European-Non Finnish (NFE) AF: 0.824 AC: 915000 AN: 1111042

Other (OTH) AF: 0.836 AC: 50318 AN: 60196

GnomAD4 genome AF: 0.832 AC: 126572 AN: 152152 Hom.: 52807 Cov.: 32 AF XY: 0.834 AC XY: 62009 AN XY: 74382

African (AFR) AF: 0.789 AC: 32737 AN: 41488

American (AMR) AF: 0.883 AC: 13506 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.814 AC: 2826 AN: 3470

East Asian (EAS) AF: 0.991 AC: 5128 AN: 5176

South Asian (SAS) AF: 0.888 AC: 4287 AN: 4826

European-Finnish (FIN) AF: 0.822 AC: 8713 AN: 10598

Middle Eastern (MID) AF: 0.863 AC: 252 AN: 292

European-Non Finnish (NFE) AF: 0.831 AC: 56511 AN: 67984

Other (OTH) AF: 0.858 AC: 1815 AN: 2116

Alfa AF: 0.798 Hom.: 3779

Bravo AF: 0.834

Asia WGS AF: 0.923 AC: 3211 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hypercholesterolemia, familial, 1 (1)
-	-	1	not provided (1)
1	-	-	Short fetal femur length (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.6
DANN	Benign	0.74
PhyloP100		-0.38
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: rs585131; hg19: chr1-55524116;