chr1-55061662-C-T

Position:

• chr1-55061662-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_174936.4(PCSK9):​c.1863+106C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00353 in 1,425,278 control chromosomes in the GnomAD database, including 125 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 0.017 (64 hom., cov: 34)
  • Exomes 𝑓: 0.0019 (61 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.525

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0553 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1863+106C>T		intron_variant		ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.1863+106C>T		intron_variant		1	NM_174936.4	ENSP00000303208	P2

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2548 AN: 152172 Hom.: 63 Cov.: 34

Gnomad AFR AF: 0.0572

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00668

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0124

GnomAD4 exome AF: 0.00195 AC: 2476 AN: 1272988 Hom.: 61 AF XY: 0.00166 AC XY: 1051 AN XY: 633324

Gnomad4 AFR exome AF: 0.0575

Gnomad4 AMR exome AF: 0.00321

Gnomad4 ASJ exome AF: 0.0118

Gnomad4 EAS exome AF: 0.0000570

Gnomad4 SAS exome AF: 0.000184

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000142

Gnomad4 OTH exome AF: 0.00458

GnomAD4 genome AF: 0.0168 AC: 2556 AN: 152290 Hom.: 64 Cov.: 34 AF XY: 0.0163 AC XY: 1212 AN XY: 74466

Gnomad4 AFR AF: 0.0572

Gnomad4 AMR AF: 0.00667

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00296 Hom.: 0

Bravo AF: 0.0190

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.11
DANN	Benign	0.91

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: rs28362278; hg19: chr1-55527335;