rs11800265

Variant names:

• chr1-55052614-G-A
• rs11800265
• NM_174936.4:c.658-36G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-55052614-G-A
• chr1-55052614-G-C
• chr1-55052614-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_174936.4(PCSK9):​c.658-36G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0424 in 1,610,610 control chromosomes in the GnomAD database, including 1,652 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.039 (135 hom., cov: 34)
  • Exomes 𝑓: 0.043 (1517 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:2
• Conservation: PhyloP100: 0.877
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.116 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.658-36G>A		intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.781-36G>A		intron	N/A	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.658-36G>A		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.658-36G>A		intron	N/A	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.1015-36G>A		intron	N/A	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.781-36G>A		intron	N/A	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.0394 AC: 5998 AN: 152210 Hom.: 135 Cov.: 34

Gnomad AFR AF: 0.0352

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0359

Gnomad ASJ AF: 0.0904

Gnomad EAS AF: 0.0316

Gnomad SAS AF: 0.0457

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.0427

Gnomad OTH AF: 0.0535

GnomAD2 exomes AF: 0.0417 AC: 10285 AN: 246884 AF XY: 0.0422

Gnomad AFR exome AF: 0.0340

Gnomad AMR exome AF: 0.0285

Gnomad ASJ exome AF: 0.0947

Gnomad EAS exome AF: 0.0317

Gnomad FIN exome AF: 0.0215

Gnomad NFE exome AF: 0.0455

Gnomad OTH exome AF: 0.0510

GnomAD4 exome AF: 0.0427 AC: 62301 AN: 1458282 Hom.: 1517 Cov.: 38 AF XY: 0.0429 AC XY: 31113 AN XY: 724930

African (AFR) AF: 0.0365 AC: 1222 AN: 33454

American (AMR) AF: 0.0294 AC: 1312 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0940 AC: 2449 AN: 26052

East Asian (EAS) AF: 0.0274 AC: 1087 AN: 39640

South Asian (SAS) AF: 0.0445 AC: 3834 AN: 86134

European-Finnish (FIN) AF: 0.0235 AC: 1234 AN: 52478

Middle Eastern (MID) AF: 0.124 AC: 712 AN: 5752

European-Non Finnish (NFE) AF: 0.0429 AC: 47611 AN: 1109822

Other (OTH) AF: 0.0471 AC: 2840 AN: 60276

GnomAD4 genome AF: 0.0394 AC: 6006 AN: 152328 Hom.: 135 Cov.: 34 AF XY: 0.0378 AC XY: 2814 AN XY: 74488

African (AFR) AF: 0.0353 AC: 1467 AN: 41580

American (AMR) AF: 0.0359 AC: 549 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0904 AC: 314 AN: 3472

East Asian (EAS) AF: 0.0315 AC: 163 AN: 5182

South Asian (SAS) AF: 0.0455 AC: 220 AN: 4830

European-Finnish (FIN) AF: 0.0174 AC: 185 AN: 10620

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.0427 AC: 2906 AN: 68018

Other (OTH) AF: 0.0544 AC: 115 AN: 2114

Alfa AF: 0.0476 Hom.: 49

Bravo AF: 0.0417

Asia WGS AF: 0.0500 AC: 174 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hypercholesterolemia, familial, 1 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.9
DANN	Benign	0.74
PhyloP100		0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs11800265; hg19: chr1-55518287; COSMIC: COSV107390143;