chr1-55058181-C-T

Variant names:

• chr1-55058181-C-T
• rs28362262
• NM_174936.4:c.1326C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_174936.4(PCSK9):​c.1326C>T​(p.Ala442Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,613,342 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (15 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (14 hom.)
• Consequence: PCSK9 NM_174936.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.393
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 1-55058181-C-T is Benign according to our data. Variant chr1-55058181-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 297701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.393 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00794 (1210/152320) while in subpopulation AFR AF = 0.028 (1162/41564). AF 95% confidence interval is 0.0266. There are 15 homozygotes in GnomAd4. There are 563 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 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.1326C>T	p.Ala442Ala	synonymous	Exon 8 of 12	NP_777596.2
	PCSK9	NM_001407240.1		c.1449C>T	p.Ala483Ala	synonymous	Exon 9 of 13	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.1326C>T	p.Ala442Ala	synonymous	Exon 8 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.1326C>T	p.Ala442Ala	synonymous	Exon 8 of 12	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.1683C>T	p.Ala561Ala	synonymous	Exon 8 of 12	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.1449C>T	p.Ala483Ala	synonymous	Exon 9 of 13	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.00795 AC: 1210 AN: 152202 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0280

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00217 AC: 542 AN: 249870 AF XY: 0.00165

Gnomad AFR exome AF: 0.0274

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.000598

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000338

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.000839 AC: 1226 AN: 1461022 Hom.: 14 Cov.: 33 AF XY: 0.000706 AC XY: 513 AN XY: 726832

African (AFR) AF: 0.0282 AC: 944 AN: 33480

American (AMR) AF: 0.00163 AC: 73 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52634

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5750

European-Non Finnish (NFE) AF: 0.0000737 AC: 82 AN: 1111970

Other (OTH) AF: 0.00166 AC: 100 AN: 60386

GnomAD4 genome AF: 0.00794 AC: 1210 AN: 152320 Hom.: 15 Cov.: 33 AF XY: 0.00756 AC XY: 563 AN XY: 74470

African (AFR) AF: 0.0280 AC: 1162 AN: 41564

American (AMR) AF: 0.00170 AC: 26 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68026

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00456 Hom.: 2

Bravo AF: 0.00884

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.54
PhyloP100		-0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs28362262; hg19: chr1-55523854; COSMIC: COSV56160480;