NM_174936.4:c.60_65delGCTGCT

Variant names:

• chr1-55039879-ACTGCTG-A
• rs35574083
• NM_174936.4:c.60_65delGCTGCT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3 BP6

The NM_174936.4(PCSK9):​c.60_65delGCTGCT​(p.Leu21_Leu22del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000027 in 1,557,934 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: PCSK9 NM_174936.4 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.04
• Publications: 14 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: Likely_benign. The variant received -2 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_174936.4
• BP6: Variant 1-55039879-ACTGCTG-A is Benign according to our data. Variant chr1-55039879-ACTGCTG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 627764.

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.60_65delGCTGCT	p.Leu21_Leu22del	disruptive_inframe_deletion	Exon 1 of 12	NP_777596.2
	PCSK9	NM_001407240.1		c.60_65delGCTGCT	p.Leu21_Leu22del	disruptive_inframe_deletion	Exon 1 of 13	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.60_65delGCTGCT	p.Leu21_Leu22del	disruptive_inframe_deletion	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.60_65delGCTGCT	p.Leu21_Leu22del	disruptive_inframe_deletion	Exon 1 of 12	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.417_422delGCTGCT	p.Leu140_Leu141del	disruptive_inframe_deletion	Exon 1 of 12	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.60_65delGCTGCT	p.Leu21_Leu22del	disruptive_inframe_deletion	Exon 1 of 13	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152070 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000559 AC: 9 AN: 161082 AF XY: 0.0000812

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000417

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000292 AC: 41 AN: 1405748 Hom.: 0 AF XY: 0.0000317 AC XY: 22 AN XY: 694296

African (AFR) AF: 0.0000311 AC: 1 AN: 32168

American (AMR) AF: 0.0000273 AC: 1 AN: 36632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25156

East Asian (EAS) AF: 0.000244 AC: 9 AN: 36930

South Asian (SAS) AF: 0.000238 AC: 19 AN: 79788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48878

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4748

European-Non Finnish (NFE) AF: 0.00000831 AC: 9 AN: 1083136

Other (OTH) AF: 0.0000343 AC: 2 AN: 58312

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74422

African (AFR) AF: 0.00 AC: 0 AN: 41526

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 92

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	1	-	Familial hypercholesterolemia (1)
-	1	-	Hypercholesterolemia, autosomal dominant, 3 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
Mutation Taster		=131/69	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35574083; hg19: chr1-55505552; COSMIC: COSV108126152;