rs7552350

chr1-55052525-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_174936.4(PCSK9):c.657+114C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,535,416 control chromosomes in the GnomAD database, including 19,261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (2147 hom., cov: 34)
  • Exomes 𝑓: 0.16 (17114 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00500

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-55052525-C-A is Benign according to our data. Variant chr1-55052525-C-A is described in ClinVar as [Benign]. Clinvar id is 265929.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-55052525-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4	c.657+114C>A		intron_variant		ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5	c.657+114C>A		intron_variant		1	NM_174936.4	P2

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24575 AN: 150374 Hom.: 2142 Cov.: 34

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.0496

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0880

Gnomad MID AF: 0.148

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.171

GnomAD4 exome AF: 0.157 AC: 217594 AN: 1384924 Hom.: 17114 Cov.: 36 AF XY: 0.157 AC XY: 107935 AN XY: 688098

Gnomad4 AFR exome AF: 0.214

Gnomad4 AMR exome AF: 0.103

Gnomad4 ASJ exome AF: 0.183

Gnomad4 EAS exome AF: 0.0400

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.0922

Gnomad4 NFE exome AF: 0.167

Gnomad4 OTH exome AF: 0.153

GnomAD4 genome AF: 0.163 AC: 24599 AN: 150492 Hom.: 2147 Cov.: 34 AF XY: 0.157 AC XY: 11539 AN XY: 73358

Gnomad4 AFR AF: 0.204

Gnomad4 AMR AF: 0.142

Gnomad4 ASJ AF: 0.175

Gnomad4 EAS AF: 0.0497

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.0880

Gnomad4 NFE AF: 0.165

Gnomad4 OTH AF: 0.169

Alfa AF: 0.161 Hom.: 264

Bravo AF: 0.168

Asia WGS AF: 0.0860 AC: 300 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:1

Benign, criteria provided, single submitter

research

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Mar 01, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	4.2
Dann	Benign	0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs7552350; hg19: chr1-55518198; COSMIC: COSV56162577;