rs11806638

Variant names:

• chr1-55052487-C-A
• rs11806638
• NM_174936.4:c.657+76C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-55052487-C-A
• chr1-55052487-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.657+76C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0695 in 1,606,636 control chromosomes in the GnomAD database, including 6,838 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2374 hom., cov: 32)
  • Exomes 𝑓: 0.063 (4464 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.44
• Publications: 17 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=-0.87).
• BP6: Variant 1-55052487-C-A is Benign according to our data. Variant chr1-55052487-C-A is described in ClinVar as [Benign]. Clinvar id is 265924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.657+76C>A		intron_variant	Intron 4 of 11	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.657+76C>A		intron_variant	Intron 4 of 11	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.132 AC: 19845 AN: 150198 Hom.: 2365 Cov.: 32

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.0442

Gnomad AMR AF: 0.0697

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.0315

Gnomad SAS AF: 0.0665

Gnomad FIN AF: 0.0377

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.0569

Gnomad OTH AF: 0.128

GnomAD4 exome AF: 0.0630 AC: 91709 AN: 1456318 Hom.: 4464 Cov.: 33 AF XY: 0.0623 AC XY: 45123 AN XY: 724344

African (AFR) AF: 0.330 AC: 11025 AN: 33404

American (AMR) AF: 0.0499 AC: 2221 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 3496 AN: 26092

East Asian (EAS) AF: 0.0265 AC: 1050 AN: 39598

South Asian (SAS) AF: 0.0628 AC: 5395 AN: 85894

European-Finnish (FIN) AF: 0.0421 AC: 2190 AN: 52006

Middle Eastern (MID) AF: 0.148 AC: 844 AN: 5710

European-Non Finnish (NFE) AF: 0.0547 AC: 60695 AN: 1108840

Other (OTH) AF: 0.0796 AC: 4793 AN: 60240

GnomAD4 genome AF: 0.132 AC: 19888 AN: 150318 Hom.: 2374 Cov.: 32 AF XY: 0.128 AC XY: 9375 AN XY: 73280

African (AFR) AF: 0.323 AC: 13355 AN: 41400

American (AMR) AF: 0.0696 AC: 1037 AN: 14894

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 448 AN: 3462

East Asian (EAS) AF: 0.0314 AC: 156 AN: 4976

South Asian (SAS) AF: 0.0662 AC: 308 AN: 4656

European-Finnish (FIN) AF: 0.0377 AC: 388 AN: 10290

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.0569 AC: 3836 AN: 67376

Other (OTH) AF: 0.128 AC: 265 AN: 2064

Alfa AF: 0.0526 Hom.: 115

Bravo AF: 0.141

Asia WGS AF: 0.0870 AC: 302 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.089
DANN	Benign	0.73
PhyloP100		-3.4
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: rs11806638; hg19: chr1-55518160;