NM_002594.5:c.10G>T

Variant names:

• chr20-17227315-G-T
• NM_002594.5:c.10G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002594.5(PCSK2):​c.10G>T​(p.Gly4Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PCSK2 NM_002594.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.05

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK2	NM_002594.5	c.10G>T	p.Gly4Cys	missense_variant	Exon 1 of 12	ENST00000262545.7	NP_002585.2
PCSK2	NM_001201529.3	c.10G>T	p.Gly4Cys	missense_variant	Exon 1 of 11		NP_001188458.1
PCSK2	NM_001201528.2	c.-33-15G>T		intron_variant	Intron 1 of 12		NP_001188457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK2	ENST00000262545.7	c.10G>T	p.Gly4Cys	missense_variant	Exon 1 of 12	1	NM_002594.5	ENSP00000262545.2
PCSK2	ENST00000377899.5	c.-33-15G>T		intron_variant	Intron 1 of 12	1		ENSP00000367131.1
PCSK2	ENST00000536609.1	c.10G>T	p.Gly4Cys	missense_variant	Exon 1 of 11	2		ENSP00000437458.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.069	T;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.90	L;L
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.37	N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.030	D;D
Polyphen		1.0	D;.
Vest4		0.59
MutPred		0.42		Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);
MVP		0.76
MPC		0.27
ClinPred		0.82	D
GERP RS		5.4
Varity_R		0.22
gMVP		0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-17207960;