1-55057360-A-G

Variant names:

• chr1-55057360-A-G
• rs509504
• NM_174936.4:c.1026A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_174936.4(PCSK9):​c.1026A>G​(p.Gln342Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.997 in 1,614,038 control chromosomes in the GnomAD database, including 802,215 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.98 (73721 hom., cov: 34)
  • Exomes 𝑓: 1.0 (728494 hom.)
• Consequence: PCSK9 NM_174936.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:16
• Conservation: PhyloP100: 0.988
• Publications: 26 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 1-55057360-A-G is Benign according to our data. Variant chr1-55057360-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 262899.
• BP7: Synonymous conserved (PhyloP=0.988 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	NM_174936.4	MANE Select	c.1026A>G	p.Gln342Gln	synonymous	Exon 7 of 12	NP_777596.2
	PCSK9	NM_001407240.1		c.1149A>G	p.Gln383Gln	synonymous	Exon 8 of 13	NP_001394169.1
	PCSK9	NM_001407241.1		c.1026A>G	p.Gln342Gln	synonymous	Exon 7 of 12	NP_001394170.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.1026A>G	p.Gln342Gln	synonymous	Exon 7 of 12	ENSP00000303208.5
	PCSK9	ENST00000710286.1		c.1383A>G	p.Gln461Gln	synonymous	Exon 7 of 12	ENSP00000518176.1
	PCSK9	ENST00000713786.1		c.1149A>G	p.Gln383Gln	synonymous	Exon 8 of 13	ENSP00000519088.1

Frequencies

GnomAD3 genomes AF: 0.984 AC: 149710 AN: 152208 Hom.: 73670 Cov.: 34

Gnomad AFR AF: 0.942

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.996

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.988

GnomAD2 exomes AF: 0.996 AC: 250062 AN: 251170 AF XY: 0.997

Gnomad AFR exome AF: 0.941

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.998 AC: 1459285 AN: 1461712 Hom.: 728494 Cov.: 86 AF XY: 0.999 AC XY: 726126 AN XY: 727176

African (AFR) AF: 0.941 AC: 31504 AN: 33480

American (AMR) AF: 0.997 AC: 44579 AN: 44724

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26136 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39700 AN: 39700

South Asian (SAS) AF: 1.00 AC: 86245 AN: 86258

European-Finnish (FIN) AF: 1.00 AC: 53252 AN: 53252

Middle Eastern (MID) AF: 0.998 AC: 5759 AN: 5768

European-Non Finnish (NFE) AF: 1.00 AC: 1111920 AN: 1112002

Other (OTH) AF: 0.997 AC: 60190 AN: 60392

GnomAD4 genome AF: 0.984 AC: 149820 AN: 152326 Hom.: 73721 Cov.: 34 AF XY: 0.984 AC XY: 73297 AN XY: 74482

African (AFR) AF: 0.942 AC: 39169 AN: 41574

American (AMR) AF: 0.996 AC: 15242 AN: 15310

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5166 AN: 5166

South Asian (SAS) AF: 1.00 AC: 4821 AN: 4822

European-Finnish (FIN) AF: 1.00 AC: 10628 AN: 10628

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68029 AN: 68034

Other (OTH) AF: 0.988 AC: 2088 AN: 2114

Alfa AF: 0.985 Hom.: 59662

Bravo AF: 0.981

Asia WGS AF: 0.997 AC: 3467 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	Hypercholesterolemia, autosomal dominant, 3 (5)
-	-	4	not specified (4)
-	1	2	Hypercholesterolemia, familial, 1 (3)
-	-	2	Familial hypercholesterolemia (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypobetalipoproteinemia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.5
DANN	Benign	0.57
PhyloP100		0.99
Mutation Taster		=99/1	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: rs509504; hg19: chr1-55523033; COSMIC: COSV108126148;