chr1-55039995-C-T

Variant names:

• chr1-55039995-C-T
• rs11583680
• NM_174936.4:c.158C>T

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.158C>T​(p.Ala53Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,578,058 control chromosomes in the GnomAD database, including 13,709 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A53G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.094 (828 hom., cov: 34)
  • Exomes 𝑓: 0.13 (12881 hom.)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:21
• Conservation: PhyloP100: 1.52
• Publications: 92 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010536611).
• BP6: Variant 1-55039995-C-T is Benign according to our data. Variant chr1-55039995-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.141 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	NM_174936.4	MANE Select	c.158C>T	p.Ala53Val	missense	Exon 1 of 12	NP_777596.2
	PCSK9	NM_001407240.1		c.158C>T	p.Ala53Val	missense	Exon 1 of 13	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.158C>T	p.Ala53Val	missense	Exon 1 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.158C>T	p.Ala53Val	missense	Exon 1 of 12	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.515C>T	p.Ala172Val	missense	Exon 1 of 12	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.158C>T	p.Ala53Val	missense	Exon 1 of 13	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.0943 AC: 14354 AN: 152204 Hom.: 823 Cov.: 34

Gnomad AFR AF: 0.0235

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.0752

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.0863

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.0999

GnomAD2 exomes AF: 0.114 AC: 21927 AN: 192322 AF XY: 0.119

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.0604

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.122

Gnomad FIN exome AF: 0.0908

Gnomad NFE exome AF: 0.135

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.131 AC: 187059 AN: 1425738 Hom.: 12881 Cov.: 31 AF XY: 0.132 AC XY: 93384 AN XY: 705788

African (AFR) AF: 0.0190 AC: 621 AN: 32728

American (AMR) AF: 0.0643 AC: 2580 AN: 40152

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 3928 AN: 25478

East Asian (EAS) AF: 0.127 AC: 4805 AN: 37728

South Asian (SAS) AF: 0.149 AC: 12047 AN: 81068

European-Finnish (FIN) AF: 0.0949 AC: 4769 AN: 50230

Middle Eastern (MID) AF: 0.0991 AC: 466 AN: 4700

European-Non Finnish (NFE) AF: 0.138 AC: 150702 AN: 1094698

Other (OTH) AF: 0.121 AC: 7141 AN: 58956

GnomAD4 genome AF: 0.0942 AC: 14351 AN: 152320 Hom.: 828 Cov.: 34 AF XY: 0.0919 AC XY: 6841 AN XY: 74480

African (AFR) AF: 0.0234 AC: 972 AN: 41578

American (AMR) AF: 0.0750 AC: 1148 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 540 AN: 3470

East Asian (EAS) AF: 0.116 AC: 598 AN: 5172

South Asian (SAS) AF: 0.150 AC: 723 AN: 4828

European-Finnish (FIN) AF: 0.0863 AC: 917 AN: 10626

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.132 AC: 8947 AN: 68026

Other (OTH) AF: 0.101 AC: 214 AN: 2114

Alfa AF: 0.124 Hom.: 2271

Bravo AF: 0.0929

TwinsUK AF: 0.124 AC: 461

ALSPAC AF: 0.143 AC: 553

ESP6500AA AF: 0.0288 AC: 126

ESP6500EA AF: 0.130 AC: 1111

ExAC AF: 0.0935 AC: 11112

Asia WGS AF: 0.128 AC: 445 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	6	Hypercholesterolemia, autosomal dominant, 3 (7)
-	-	5	Hypercholesterolemia, familial, 1 (5)
-	-	4	not specified (4)
-	-	2	Familial hypercholesterolemia (2)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypobetalipoproteinemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.095	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.63	N
PhyloP100		1.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.065
Sift	Benign	0.31	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.018
MPC		0.22
ClinPred		0.0088	T
GERP RS		2.2
PromoterAI		0.0088	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.083
gMVP		0.72
Mutation Taster		=91/9	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: rs11583680; hg19: chr1-55505668; COSMIC: COSV100134955;