rs28385710

Variant names:

• chr1-55052745-C-T
• rs28385710
• NM_174936.4:c.753C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-55052745-C-T
• chr1-55052745-C-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_174936.4(PCSK9):​c.753C>T​(p.Arg251Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,613,204 control chromosomes in the GnomAD database, including 32 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 0.0028 (1 hom., cov: 35)
  • Exomes 𝑓: 0.0032 (31 hom.)
• Consequence: PCSK9 NM_174936.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:15
• Conservation: PhyloP100: -4.49
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 1-55052745-C-T is Benign according to our data. Variant chr1-55052745-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 262907.
• BP7: Synonymous conserved (PhyloP=-4.49 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00283 (431/152360) while in subpopulation SAS AF = 0.0226 (109/4832). AF 95% confidence interval is 0.0191. There are 1 homozygotes in GnomAd4. There are 239 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 31 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.753C>T	p.Arg251Arg	synonymous	Exon 5 of 12	NP_777596.2
	PCSK9	NM_001407240.1		c.876C>T	p.Arg292Arg	synonymous	Exon 6 of 13	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.753C>T	p.Arg251Arg	synonymous	Exon 5 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.753C>T	p.Arg251Arg	synonymous	Exon 5 of 12	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.1110C>T	p.Arg370Arg	synonymous	Exon 5 of 12	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.876C>T	p.Arg292Arg	synonymous	Exon 6 of 13	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.00284 AC: 432 AN: 152242 Hom.: 1 Cov.: 35

Gnomad AFR AF: 0.000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0227

Gnomad FIN AF: 0.000752

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00285

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00378 AC: 942 AN: 248954 AF XY: 0.00465

Gnomad AFR exome AF: 0.000559

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.000599

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000971

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.00459

GnomAD4 exome AF: 0.00325 AC: 4747 AN: 1460844 Hom.: 31 Cov.: 82 AF XY: 0.00368 AC XY: 2671 AN XY: 726746

African (AFR) AF: 0.000388 AC: 13 AN: 33478

American (AMR) AF: 0.00145 AC: 65 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0180 AC: 1555 AN: 86258

European-Finnish (FIN) AF: 0.000763 AC: 40 AN: 52432

Middle Eastern (MID) AF: 0.00746 AC: 43 AN: 5766

European-Non Finnish (NFE) AF: 0.00249 AC: 2770 AN: 1111980

Other (OTH) AF: 0.00399 AC: 241 AN: 60380

GnomAD4 genome AF: 0.00283 AC: 431 AN: 152360 Hom.: 1 Cov.: 35 AF XY: 0.00321 AC XY: 239 AN XY: 74510

African (AFR) AF: 0.000721 AC: 30 AN: 41588

American (AMR) AF: 0.00503 AC: 77 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0226 AC: 109 AN: 4832

European-Finnish (FIN) AF: 0.000752 AC: 8 AN: 10632

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

European-Non Finnish (NFE) AF: 0.00285 AC: 194 AN: 68032

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00242 Hom.: 8

Bravo AF: 0.00271

Asia WGS AF: 0.00549 AC: 20 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00279

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.52
DANN	Benign	0.89
PhyloP100		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=94/6	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: rs28385710; hg19: chr1-55518418; COSMIC: COSV107390144;