rs624612

Variant names:

• chr1-55052210-C-G
• rs624612
• NM_174936.4:c.524-68C>G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_174936.4(PCSK9):​c.524-68C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 1,603,938 control chromosomes in the GnomAD database, including 154,167 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.35 (11878 hom., cov: 32)
  • Exomes 𝑓: 0.43 (142289 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.30

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-55052210-C-G is Benign according to our data. Variant chr1-55052210-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.524-68C>G		intron_variant	Intron 3 of 11	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.524-68C>G		intron_variant	Intron 3 of 11	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53753 AN: 151908 Hom.: 11870 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.333

Gnomad EAS AF: 0.715

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.393

GnomAD4 exome AF: 0.433 AC: 628076 AN: 1451914 Hom.: 142289 Cov.: 30 AF XY: 0.430 AC XY: 310991 AN XY: 722824

Gnomad4 AFR exome AF: 0.0839

Gnomad4 AMR exome AF: 0.688

Gnomad4 ASJ exome AF: 0.324

Gnomad4 EAS exome AF: 0.719

Gnomad4 SAS exome AF: 0.415

Gnomad4 FIN exome AF: 0.403

Gnomad4 NFE exome AF: 0.429

Gnomad4 OTH exome AF: 0.427

GnomAD4 genome AF: 0.354 AC: 53774 AN: 152024 Hom.: 11878 Cov.: 32 AF XY: 0.359 AC XY: 26673 AN XY: 74306

Gnomad4 AFR AF: 0.100

Gnomad4 AMR AF: 0.558

Gnomad4 ASJ AF: 0.333

Gnomad4 EAS AF: 0.715

Gnomad4 SAS AF: 0.431

Gnomad4 FIN AF: 0.393

Gnomad4 NFE AF: 0.425

Gnomad4 OTH AF: 0.397

Alfa AF: 0.380 Hom.: 1691

Bravo AF: 0.359

Asia WGS AF: 0.546 AC: 1897 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.069
DANN	Benign	0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs624612; hg19: chr1-55517883;