1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGT

Variant names:

• chr1-55058666-CGTGTGTGTGTGT-C
• rs35115360
• NM_174936.4:c.1503+60_1503+71delGTGTGTGTGTGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_174936.4(PCSK9):​c.1503+60_1503+71delGTGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (787 hom., cov: 0)
  • Exomes 𝑓: 0.083 (626 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.564
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 1-55058666-CGTGTGTGTGTGT-C is Benign according to our data. Variant chr1-55058666-CGTGTGTGTGTGT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 492238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.132 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.1503+60_1503+71delGTGTGTGTGTGT		intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.1626+60_1626+71delGTGTGTGTGTGT		intron	N/A	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.1503+60_1503+71delGTGTGTGTGTGT		intron	N/A	NP_001394170.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.1503+20_1503+31delGTGTGTGTGTGT		intron	N/A	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.1860+20_1860+31delGTGTGTGTGTGT		intron	N/A	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.1626+20_1626+31delGTGTGTGTGTGT		intron	N/A	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.0970 AC: 13799 AN: 142270 Hom.: 785 Cov.: 0

Gnomad AFR AF: 0.0975

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.0303

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.0457

Gnomad FIN AF: 0.0980

Gnomad MID AF: 0.0608

Gnomad NFE AF: 0.0942

Gnomad OTH AF: 0.0747

GnomAD2 exomes AF: 0.0519 AC: 7738 AN: 149146 AF XY: 0.0477

Gnomad AFR exome AF: 0.0658

Gnomad AMR exome AF: 0.0832

Gnomad ASJ exome AF: 0.0176

Gnomad EAS exome AF: 0.0827

Gnomad FIN exome AF: 0.0550

Gnomad NFE exome AF: 0.0445

Gnomad OTH exome AF: 0.0534

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0826 AC: 113841 AN: 1377520 Hom.: 626 AF XY: 0.0803 AC XY: 54873 AN XY: 683266

African (AFR) AF: 0.0877 AC: 2754 AN: 31414

American (AMR) AF: 0.117 AC: 4595 AN: 39276

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 734 AN: 24682

East Asian (EAS) AF: 0.0902 AC: 3303 AN: 36608

South Asian (SAS) AF: 0.0436 AC: 3521 AN: 80762

European-Finnish (FIN) AF: 0.0807 AC: 3846 AN: 47664

Middle Eastern (MID) AF: 0.0361 AC: 144 AN: 3986

European-Non Finnish (NFE) AF: 0.0857 AC: 90562 AN: 1056140

Other (OTH) AF: 0.0769 AC: 4382 AN: 56988

GnomAD4 genome AF: 0.0970 AC: 13812 AN: 142352 Hom.: 787 Cov.: 0 AF XY: 0.0963 AC XY: 6641 AN XY: 68962

African (AFR) AF: 0.0975 AC: 3687 AN: 37824

American (AMR) AF: 0.137 AC: 1996 AN: 14586

Ashkenazi Jewish (ASJ) AF: 0.0303 AC: 102 AN: 3364

East Asian (EAS) AF: 0.111 AC: 526 AN: 4736

South Asian (SAS) AF: 0.0446 AC: 195 AN: 4372

European-Finnish (FIN) AF: 0.0980 AC: 892 AN: 9104

Middle Eastern (MID) AF: 0.0625 AC: 17 AN: 272

European-Non Finnish (NFE) AF: 0.0942 AC: 6146 AN: 65260

Other (OTH) AF: 0.0737 AC: 144 AN: 1954

Alfa AF: 0.0694 Hom.: 1122

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hypercholesterolemia, familial, 1 (2)
-	-	1	Familial hypercholesterolemia (1)
-	-	1	Hypercholesterolemia, autosomal dominant, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.56
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs35115360; hg19: chr1-55524339;