chr1-55039879-A-ACTG

Variant names:

• chr1-55039879-A-ACTG
• rs35574083
• NM_174936.4:c.63_65dupGCT

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_174936.4(PCSK9):​c.63_65dupGCT​(p.Leu22dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,557,874 control chromosomes in the GnomAD database, including 14,501 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L22L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (1818 hom., cov: 31)
  • Exomes 𝑓: 0.14 (12683 hom.)
• Consequence: PCSK9 NM_174936.4 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.246
• 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: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_174936.4
• BP6: Variant 1-55039879-A-ACTG is Benign according to our data. Variant chr1-55039879-A-ACTG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

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.63_65dupGCT	p.Leu22dup	disruptive_inframe_insertion	Exon 1 of 12	NP_777596.2
	PCSK9	NM_001407240.1		c.63_65dupGCT	p.Leu22dup	disruptive_inframe_insertion	Exon 1 of 13	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.63_65dupGCT	p.Leu22dup	disruptive_inframe_insertion	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.63_65dupGCT	p.Leu22dup	disruptive_inframe_insertion	Exon 1 of 12	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.420_422dupGCT	p.Leu141dup	disruptive_inframe_insertion	Exon 1 of 12	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.63_65dupGCT	p.Leu22dup	disruptive_inframe_insertion	Exon 1 of 13	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23110 AN: 152038 Hom.: 1811 Cov.: 31

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.0863

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.143

GnomAD2 exomes AF: 0.122 AC: 19607 AN: 161082 AF XY: 0.123

Gnomad AFR exome AF: 0.180

Gnomad AMR exome AF: 0.0770

Gnomad ASJ exome AF: 0.161

Gnomad EAS exome AF: 0.115

Gnomad FIN exome AF: 0.0898

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.140 AC: 197297 AN: 1405720 Hom.: 12683 Cov.: 30 AF XY: 0.140 AC XY: 97431 AN XY: 694280

African (AFR) AF: 0.201 AC: 6452 AN: 32166

American (AMR) AF: 0.0817 AC: 2993 AN: 36632

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 4189 AN: 25156

East Asian (EAS) AF: 0.122 AC: 4506 AN: 36930

South Asian (SAS) AF: 0.146 AC: 11644 AN: 79788

European-Finnish (FIN) AF: 0.0938 AC: 4583 AN: 48876

Middle Eastern (MID) AF: 0.125 AC: 595 AN: 4746

European-Non Finnish (NFE) AF: 0.142 AC: 154204 AN: 1083118

Other (OTH) AF: 0.139 AC: 8131 AN: 58308

GnomAD4 genome AF: 0.152 AC: 23137 AN: 152154 Hom.: 1818 Cov.: 31 AF XY: 0.148 AC XY: 11020 AN XY: 74402

African (AFR) AF: 0.208 AC: 8628 AN: 41518

American (AMR) AF: 0.108 AC: 1650 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 593 AN: 3466

East Asian (EAS) AF: 0.114 AC: 591 AN: 5162

South Asian (SAS) AF: 0.150 AC: 726 AN: 4824

European-Finnish (FIN) AF: 0.0863 AC: 914 AN: 10596

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9434 AN: 67976

Other (OTH) AF: 0.144 AC: 303 AN: 2110

Alfa AF: 0.0742 Hom.: 92

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.25
Mutation Taster		=81/19	polymorphism (auto)

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: COSV56160392;