1-55060755-T-G

Variant names:

• chr1-55060755-T-G
• rs11206517
• NM_174936.4:c.1682-620T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_174936.4(PCSK9):​c.1682-620T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0809 in 152,200 control chromosomes in the GnomAD database, including 824 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.081 (824 hom., cov: 32)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.69

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1682-620T>G		intron_variant	Intron 10 of 11	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.1682-620T>G		intron_variant	Intron 10 of 11	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.0807 AC: 12275 AN: 152080 Hom.: 821 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0364

Gnomad ASJ AF: 0.0541

Gnomad EAS AF: 0.0513

Gnomad SAS AF: 0.0222

Gnomad FIN AF: 0.0455

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0394

Gnomad OTH AF: 0.0559

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0809 AC: 12313 AN: 152200 Hom.: 824 Cov.: 32 AF XY: 0.0789 AC XY: 5874 AN XY: 74404

African (AFR) AF: 0.189 AC: 7849 AN: 41502

American (AMR) AF: 0.0363 AC: 555 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0541 AC: 188 AN: 3472

East Asian (EAS) AF: 0.0510 AC: 264 AN: 5172

South Asian (SAS) AF: 0.0226 AC: 109 AN: 4826

European-Finnish (FIN) AF: 0.0455 AC: 483 AN: 10612

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0395 AC: 2684 AN: 68004

Other (OTH) AF: 0.0553 AC: 117 AN: 2114

Alfa AF: 0.0460 Hom.: 392

Bravo AF: 0.0853

Asia WGS AF: 0.0470 AC: 164 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.32
DANN	Benign	0.66
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs11206517; hg19: chr1-55526428;