rs630431

Variant names:

• chr1-55061650-G-A
• rs630431
• NM_174936.4:c.1863+94G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-55061650-G-A
• chr1-55061650-G-T

Variant summary

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

The NM_174936.4(PCSK9):​c.1863+94G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.697 in 1,476,310 control chromosomes in the GnomAD database, including 363,586 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 0.63 (32425 hom., cov: 32)
  • Exomes 𝑓: 0.70 (331161 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0410
• Publications: 16 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1863+94G>A		intron_variant	Intron 11 of 11	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.1863+94G>A		intron_variant	Intron 11 of 11	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96408 AN: 151900 Hom.: 32422 Cov.: 32

Gnomad AFR AF: 0.401

Gnomad AMI AF: 0.708

Gnomad AMR AF: 0.777

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.857

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.714

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.705

Gnomad OTH AF: 0.682

GnomAD4 exome AF: 0.704 AC: 932420 AN: 1324290 Hom.: 331161 AF XY: 0.706 AC XY: 463953 AN XY: 656862

African (AFR) AF: 0.381 AC: 11413 AN: 29962

American (AMR) AF: 0.828 AC: 29491 AN: 35612

Ashkenazi Jewish (ASJ) AF: 0.625 AC: 15428 AN: 24704

East Asian (EAS) AF: 0.859 AC: 30358 AN: 35334

South Asian (SAS) AF: 0.751 AC: 57982 AN: 77216

European-Finnish (FIN) AF: 0.717 AC: 34359 AN: 47922

Middle Eastern (MID) AF: 0.694 AC: 3776 AN: 5440

European-Non Finnish (NFE) AF: 0.702 AC: 711175 AN: 1012422

Other (OTH) AF: 0.690 AC: 38438 AN: 55678

GnomAD4 genome AF: 0.634 AC: 96431 AN: 152020 Hom.: 32425 Cov.: 32 AF XY: 0.641 AC XY: 47641 AN XY: 74316

African (AFR) AF: 0.400 AC: 16576 AN: 41464

American (AMR) AF: 0.777 AC: 11876 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.629 AC: 2182 AN: 3470

East Asian (EAS) AF: 0.857 AC: 4414 AN: 5152

South Asian (SAS) AF: 0.764 AC: 3668 AN: 4800

European-Finnish (FIN) AF: 0.714 AC: 7557 AN: 10590

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.705 AC: 47872 AN: 67944

Other (OTH) AF: 0.684 AC: 1444 AN: 2110

Alfa AF: 0.642 Hom.: 6990

Bravo AF: 0.628

Asia WGS AF: 0.769 AC: 2674 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	0.63
DANN	Benign	0.87
PhyloP100		-0.041
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs630431; hg19: chr1-55527323; COSMIC: COSV53764048; COSMIC: COSV53764048;