1-55052697-C-T

Variant names:

• chr1-55052697-C-T
• rs7552471
• NM_174936.4:c.705C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BA1

The NM_001407240.1(PCSK9):​c.828C>T​(p.Ser276Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00432 in 1,613,082 control chromosomes in the GnomAD database, including 268 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 0.022 (127 hom., cov: 35)
  • Exomes 𝑓: 0.0024 (141 hom.)
• Consequence: PCSK9 NM_001407240.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: -1.05
• 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, 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 1-55052697-C-T is Benign according to our data. Variant chr1-55052697-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 265932.
• BP7: Synonymous conserved (PhyloP=-1.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0752 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407240.1. 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.705C>T	p.Ser235Ser	synonymous	Exon 5 of 12	NP_777596.2
	PCSK9	NM_001407240.1		c.828C>T	p.Ser276Ser	synonymous	Exon 6 of 13	NP_001394169.1
	PCSK9	NM_001407241.1		c.705C>T	p.Ser235Ser	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.705C>T	p.Ser235Ser	synonymous	Exon 5 of 12	ENSP00000303208.5
	PCSK9	ENST00000710286.1		c.1062C>T	p.Ser354Ser	synonymous	Exon 5 of 12	ENSP00000518176.1
	PCSK9	ENST00000713786.1		c.828C>T	p.Ser276Ser	synonymous	Exon 6 of 13	ENSP00000519088.1

Frequencies

GnomAD3 genomes AF: 0.0224 AC: 3405 AN: 152210 Hom.: 127 Cov.: 35

Gnomad AFR AF: 0.0773

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00884

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.00584 AC: 1454 AN: 249132 AF XY: 0.00437

Gnomad AFR exome AF: 0.0808

Gnomad AMR exome AF: 0.00313

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.000286

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00243 AC: 3551 AN: 1460754 Hom.: 141 Cov.: 82 AF XY: 0.00212 AC XY: 1538 AN XY: 726682

African (AFR) AF: 0.0830 AC: 2778 AN: 33480

American (AMR) AF: 0.00434 AC: 194 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26118

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

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86230

European-Finnish (FIN) AF: 0.000133 AC: 7 AN: 52518

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5766

European-Non Finnish (NFE) AF: 0.000152 AC: 169 AN: 1111872

Other (OTH) AF: 0.00578 AC: 349 AN: 60370

GnomAD4 genome AF: 0.0224 AC: 3419 AN: 152328 Hom.: 127 Cov.: 35 AF XY: 0.0219 AC XY: 1634 AN XY: 74484

African (AFR) AF: 0.0775 AC: 3220 AN: 41574

American (AMR) AF: 0.00882 AC: 135 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68026

Other (OTH) AF: 0.0189 AC: 40 AN: 2112

Alfa AF: 0.0129 Hom.: 29

Bravo AF: 0.0257

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	11
DANN	Benign	0.90
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=98/2	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: rs7552471; hg19: chr1-55518370;