1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant names:

• chr1-55058666-C-CGTGT
• rs35115360
• NM_174936.4:c.1503+68_1503+71dupGTGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_174936.4(PCSK9):​c.1503+68_1503+71dupGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 0)
  • Exomes 𝑓: 0.00094 (0 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.20
• 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-C-CGTGT is Benign according to our data. Variant chr1-55058666-C-CGTGT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 928567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00296 (422/142496) while in subpopulation AFR AF = 0.00425 (161/37860). AF 95% confidence interval is 0.00372. There are 2 homozygotes in GnomAd4. There are 201 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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+68_1503+71dupGTGT		intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.1626+68_1626+71dupGTGT		intron	N/A	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.1503+68_1503+71dupGTGT		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+19_1503+20insGTGT		intron	N/A	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.1860+19_1860+20insGTGT		intron	N/A	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.1626+19_1626+20insGTGT		intron	N/A	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 421 AN: 142416 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00424

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00110

Gnomad ASJ AF: 0.000595

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000914

Gnomad FIN AF: 0.00536

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00286

Gnomad OTH AF: 0.00154

GnomAD4 exome AF: 0.000942 AC: 1310 AN: 1390592 Hom.: 0 Cov.: 0 AF XY: 0.000999 AC XY: 689 AN XY: 689450

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00143 AC: 45 AN: 31562

American (AMR) AF: 0.000860 AC: 34 AN: 39530

Ashkenazi Jewish (ASJ) AF: 0.000805 AC: 20 AN: 24856

East Asian (EAS) AF: 0.000162 AC: 6 AN: 36974

South Asian (SAS) AF: 0.00139 AC: 113 AN: 81208

European-Finnish (FIN) AF: 0.00322 AC: 154 AN: 47862

Middle Eastern (MID) AF: 0.000747 AC: 3 AN: 4014

European-Non Finnish (NFE) AF: 0.000827 AC: 883 AN: 1067124

Other (OTH) AF: 0.000905 AC: 52 AN: 57462

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00296 AC: 422 AN: 142496 Hom.: 2 Cov.: 0 AF XY: 0.00291 AC XY: 201 AN XY: 69036

African (AFR) AF: 0.00425 AC: 161 AN: 37860

American (AMR) AF: 0.00110 AC: 16 AN: 14604

Ashkenazi Jewish (ASJ) AF: 0.000595 AC: 2 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: 0.00536 AC: 49 AN: 9146

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

European-Non Finnish (NFE) AF: 0.00286 AC: 187 AN: 65302

Other (OTH) AF: 0.00153 AC: 3 AN: 1956

Alfa AF: 0.00311 Hom.: 1122

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hypercholesterolemia, autosomal dominant, 3 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.2
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;