rs148612296

Variant names:

• chr1-55052279-C-T
• rs148612296
• NM_174936.4:c.525C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_174936.4(PCSK9):​c.525C>T​(p.Asp175Asp) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000273 in 1,613,960 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: PCSK9 NM_174936.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.000005629
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.468
• Publications: 6 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-55052279-C-T is Benign according to our data. Variant chr1-55052279-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 496562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.468 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00111 (169/152212) while in subpopulation AFR AF = 0.00344 (143/41526). AF 95% confidence interval is 0.00298. There are 1 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.525C>T	p.Asp175Asp	splice_region synonymous	Exon 4 of 12	NP_777596.2
	PCSK9	NM_001407240.1		c.648C>T	p.Asp216Asp	splice_region synonymous	Exon 5 of 13	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.525C>T	p.Asp175Asp	splice_region synonymous	Exon 4 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.525C>T	p.Asp175Asp	splice_region synonymous	Exon 4 of 12	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.882C>T	p.Asp294Asp	splice_region synonymous	Exon 4 of 12	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.648C>T	p.Asp216Asp	splice_region synonymous	Exon 5 of 13	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 167 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000362 AC: 91 AN: 251392 AF XY: 0.000250

Gnomad AFR exome AF: 0.00388

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000186 AC: 272 AN: 1461748 Hom.: 0 Cov.: 35 AF XY: 0.000176 AC XY: 128 AN XY: 727174

African (AFR) AF: 0.00409 AC: 137 AN: 33480

American (AMR) AF: 0.000380 AC: 17 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86258

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53282

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000504 AC: 56 AN: 1112006

Other (OTH) AF: 0.000629 AC: 38 AN: 60394

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152212 Hom.: 1 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74422

African (AFR) AF: 0.00344 AC: 143 AN: 41526

American (AMR) AF: 0.000916 AC: 14 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4816

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.0170 Hom.: 2340

Bravo AF: 0.00125

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	2	Familial hypercholesterolemia (2)
-	-	2	Hypercholesterolemia, autosomal dominant, 3 (2)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypobetalipoproteinemia (1)
-	-	1	PCSK9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.088
DANN	Benign	0.69
PhyloP100		-0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000056
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: rs148612296; hg19: chr1-55517952;