chr20-17465549-C-G

Variant names:

• chr20-17465549-C-G
• rs749157367
• NM_002594.5:c.1426C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002594.5(PCSK2):​c.1426C>G​(p.Pro476Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,424,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. P476S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PCSK2 NM_002594.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.94
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12938759).

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.1426C>G	p.Pro476Ala	missense	Exon 11 of 12	NP_002585.2
	PCSK2	NM_001201528.2		c.1369C>G	p.Pro457Ala	missense	Exon 12 of 13	NP_001188457.1	P16519-3
	PCSK2	NM_001201529.3		c.1321C>G	p.Pro441Ala	missense	Exon 10 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.1426C>G	p.Pro476Ala	missense	Exon 11 of 12	ENSP00000262545.2	P16519-1
	PCSK2	ENST00000377899.5	TSL:1	c.1369C>G	p.Pro457Ala	missense	Exon 12 of 13	ENSP00000367131.1	P16519-3
	PCSK2	ENST00000947703.1		c.1423C>G	p.Pro475Ala	missense	Exon 11 of 12	ENSP00000617762.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1424794 Hom.: 0 Cov.: 28 AF XY: 0.00000142 AC XY: 1 AN XY: 704258

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32762

American (AMR) AF: 0.00 AC: 0 AN: 42346

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23892

East Asian (EAS) AF: 0.00 AC: 0 AN: 39274

South Asian (SAS) AF: 0.00 AC: 0 AN: 80682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5580

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1089168

Other (OTH) AF: 0.00 AC: 0 AN: 58832

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.049
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.10
Sift	Benign	0.23	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.28
MutPred		0.30		Loss of ubiquitination at K478 (P = 0.0634)
MVP		0.38
MPC		0.97
ClinPred		0.44	T
GERP RS		5.7
Varity_R		0.11
gMVP		0.49
Mutation Taster		=72/28	polymorphism

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: rs749157367; hg19: chr20-17446194;