NM_174936.4:c.1503+48_1503+71delGTGTGTGTGTGTGTGTGTGTGTGT

Variant names:

• chr1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGT-C
• rs35115360
• NM_174936.4:c.1503+48_1503+71delGTGTGTGTGTGTGTGTGTGTGTGT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_174936.4(PCSK9):​c.1503+48_1503+71delGTGTGTGTGTGTGTGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000775 in 1,535,422 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 -8 ACMG points.

• BP6: Variant 1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGT-C is Benign according to our data. Variant chr1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 492232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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+48_1503+71delGTGTGTGTGTGTGTGTGTGTGTGT		intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.1626+48_1626+71delGTGTGTGTGTGTGTGTGTGTGTGT		intron	N/A	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.1503+48_1503+71delGTGTGTGTGTGTGTGTGTGTGTGT		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+43delGTGTGTGTGTGTGTGTGTGTGTGT		intron	N/A	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.1860+20_1860+43delGTGTGTGTGTGTGTGTGTGTGTGT		intron	N/A	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.1626+20_1626+43delGTGTGTGTGTGTGTGTGTGTGTGT		intron	N/A	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.000126 AC: 18 AN: 142440 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000530

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000617

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000914

Gnomad FIN AF: 0.000328

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000725 AC: 101 AN: 1392902 Hom.: 0 AF XY: 0.0000912 AC XY: 63 AN XY: 690654

African (AFR) AF: 0.0000316 AC: 1 AN: 31628

American (AMR) AF: 0.000202 AC: 8 AN: 39552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24880

East Asian (EAS) AF: 0.00 AC: 0 AN: 36988

South Asian (SAS) AF: 0.000529 AC: 43 AN: 81354

European-Finnish (FIN) AF: 0.000313 AC: 15 AN: 47988

Middle Eastern (MID) AF: 0.000249 AC: 1 AN: 4014

European-Non Finnish (NFE) AF: 0.0000225 AC: 24 AN: 1068934

Other (OTH) AF: 0.000156 AC: 9 AN: 57564

GnomAD4 genome AF: 0.000126 AC: 18 AN: 142520 Hom.: 0 Cov.: 0 AF XY: 0.000116 AC XY: 8 AN XY: 69048

African (AFR) AF: 0.0000528 AC: 2 AN: 37868

American (AMR) AF: 0.000616 AC: 9 AN: 14604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3364

East Asian (EAS) AF: 0.00 AC: 0 AN: 4740

South Asian (SAS) AF: 0.000915 AC: 4 AN: 4372

European-Finnish (FIN) AF: 0.000328 AC: 3 AN: 9152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65310

Other (OTH) AF: 0.00 AC: 0 AN: 1958

Alfa AF: 0.00 Hom.: 1122

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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

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;