1-55058539-G-A

Variant names:

• chr1-55058539-G-A
• rs146960060
• NM_174936.4:c.1395G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_174936.4(PCSK9):​c.1395G>A​(p.Ser465Ser) 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:11
• Conservation: PhyloP100: -2.21
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.095).
• BP6: Variant 1-55058539-G-A is Benign according to our data. Variant chr1-55058539-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 496558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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.1395G>A	p.Ser465Ser	synonymous	Exon 9 of 12	NP_777596.2
	PCSK9	NM_001407240.1		c.1518G>A	p.Ser506Ser	synonymous	Exon 10 of 13	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.1395G>A	p.Ser465Ser	synonymous	Exon 9 of 12	NP_001394170.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.1395G>A	p.Ser465Ser	synonymous	Exon 9 of 12	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.1752G>A	p.Ser584Ser	synonymous	Exon 9 of 12	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.1518G>A	p.Ser506Ser	synonymous	Exon 10 of 13	ENSP00000519088.1	A0AAQ5BGX4

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

GnomAD2 exomes AF: 0.000716 AC: 180 AN: 251376 AF XY: 0.000500

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 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

African (AFR) AF: 0.0103 AC: 343 AN: 33414

American (AMR) AF: 0.000335 AC: 15 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00145 AC: 6 AN: 4142

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111868

Other (OTH) AF: 0.000482 AC: 29 AN: 60224

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

African (AFR) AF: 0.00939 AC: 390 AN: 41546

American (AMR) AF: 0.000523 AC: 8 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68012

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00201 Hom.: 2

Bravo AF: 0.00300

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Familial hypercholesterolemia (2)
-	-	2	Hypercholesterolemia, autosomal dominant, 3 (2)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.50
DANN	Uncertain	0.97
PhyloP100		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=87/13	polymorphism

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