rs146960060

chr1-55058539-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_174936.4(PCSK9):c.1395G>A(p.Ser465=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000509 in 1,611,966 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S465S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 34)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: PCSK9 NM_174936.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.21

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-55058539-G-A is Benign according to our data. Variant chr1-55058539-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 496558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55058539-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00266 (405/152226) while in subpopulation AFR AF= 0.00939 (390/41546). AF 95% confidence interval is 0.00862. There are 2 homozygotes in gnomad4. There are 182 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd at 404 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4	c.1395G>A	p.Ser465=	synonymous_variant	9/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5	c.1395G>A	p.Ser465=	synonymous_variant	9/12	1	NM_174936.4	P2

Frequencies

GnomAD3 genomes AF: 0.00266 AC: 404 AN: 152108 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00939

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000716 AC: 180 AN: 251376 Hom.: 0 AF XY: 0.000500 AC XY: 68 AN XY: 135884

Gnomad AFR exome AF: 0.00991

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000284 AC: 415 AN: 1459740 Hom.: 1 Cov.: 86 AF XY: 0.000269 AC XY: 195 AN XY: 726162

Gnomad4 AFR exome AF: 0.0103

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.000482

GnomAD4 genome AF: 0.00266 AC: 405 AN: 152226 Hom.: 2 Cov.: 34 AF XY: 0.00245 AC XY: 182 AN XY: 74424

Gnomad4 AFR AF: 0.00939

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00172 Hom.: 2

Bravo AF: 0.00300

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 05, 2016	Variant summary: The PCSK9 variant, c.1395G>A (p.Ser465Ser) causes a synonymous change involving a non-conserved nucleotide with 5/5 in silico programs via Alamut predicting no significant effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest has been observed in the large, broad control population, ExAC, with an allele frequency of 118/121334 (1/1028), predominantly in the African cohort, 112/10394 (1/92), which significantly exceeds the estimated maximum expected allele frequency for a pathogenic PCSK9 variant of 1/53191. Therefore, suggesting that the variant is a common polymorphism found in population(s) of African origin. The variant of interest, to our knowledge, has not been reported in affected individuals via publications and/or reputable clinical laboratories/databases. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 17, 2023	- -

Hypercholesterolemia, autosomal dominant, 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 18, 2018

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 28, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial hypercholesterolemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.50
Dann	Uncertain	0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

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: rs146960060; hg19: chr1-55524212; COSMIC: COSV104533954;