NM_002594.5:c.397A>C

Variant names:

• chr20-17360532-A-C
• rs1408906910
• NM_002594.5:c.397A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002594.5(PCSK2):​c.397A>C​(p.Ile133Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000484 in 1,446,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I133F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PCSK2 NM_002594.5 missense, splice_region
• Scores: Splicing: ADA: 0.003964
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.21
• Publications: 0 publications found

Genes affected

PCSK2 (HGNC:8744): (proprotein convertase subtilisin/kexin type 2) 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 protein undergoes an initial autocatalytic processing event and interacts with a neuroendocrine secretory protein in the ER, exits the ER and sorts to secretory granules, where it is cleaved and catalytically activated during intracellular transport. The encoded protease is packaged into and activated in dense core secretory granules and expressed in the neuroendocrine system and brain. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. It functions in the proteolytic activation of polypeptide hormones and neuropeptides precursors. Single nucleotide polymorphisms in this gene may increase susceptibility to myocardial infarction and type 2 diabetes. This gene may also play a role in tumor development and progression. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2014]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20551717).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002594.5. 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
	PCSK2	NM_002594.5	MANE Select	c.397A>C	p.Ile133Leu	missense splice_region	Exon 4 of 12	NP_002585.2
	PCSK2	NM_001201528.2		c.340A>C	p.Ile114Leu	missense splice_region	Exon 5 of 13	NP_001188457.1	P16519-3
	PCSK2	NM_001201529.3		c.292A>C	p.Ile98Leu	missense splice_region	Exon 3 of 11	NP_001188458.1	P16519-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK2	ENST00000262545.7	TSL:1 MANE Select	c.397A>C	p.Ile133Leu	missense splice_region	Exon 4 of 12	ENSP00000262545.2	P16519-1
	PCSK2	ENST00000377899.5	TSL:1	c.340A>C	p.Ile114Leu	missense splice_region	Exon 5 of 13	ENSP00000367131.1	P16519-3
	PCSK2	ENST00000947703.1		c.397A>C	p.Ile133Leu	missense splice_region	Exon 4 of 12	ENSP00000617762.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000484 AC: 7 AN: 1446108 Hom.: 0 Cov.: 27 AF XY: 0.00000695 AC XY: 5 AN XY: 719856

African (AFR) AF: 0.00 AC: 0 AN: 33170

American (AMR) AF: 0.00 AC: 0 AN: 44342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25952

East Asian (EAS) AF: 0.00 AC: 0 AN: 39504

South Asian (SAS) AF: 0.00 AC: 0 AN: 85146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000637 AC: 7 AN: 1099224

Other (OTH) AF: 0.00 AC: 0 AN: 59828

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		6.2
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.17
Sift	Benign	0.67	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.44
MutPred		0.33		Loss of sheet (P = 0.0817)
MVP		0.15
MPC		1.0
ClinPred		0.31	T
GERP RS		4.8
Varity_R		0.14
gMVP		0.67
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0040
dbscSNV1_RF	Benign	0.13
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: rs1408906910; hg19: chr20-17341177;