20-17260300-A-G

Variant names:

• chr20-17260300-A-G
• rs1267879920
• NM_002594.5:c.238A>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002594.5(PCSK2):​c.238A>G​(p.Arg80Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,692 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (1 hom.)
• Consequence: PCSK2 NM_002594.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.55

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]

LOC105372546 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK2	NM_002594.5	c.238A>G	p.Arg80Gly	missense_variant	Exon 2 of 12	ENST00000262545.7	NP_002585.2
PCSK2	NM_001201528.2	c.181A>G	p.Arg61Gly	missense_variant	Exon 3 of 13		NP_001188457.1
PCSK2	NM_001201529.3	c.177+32818A>G		intron_variant	Intron 1 of 10		NP_001188458.1
LOC105372546	XR_007067540.1	n.253+3764T>C		intron_variant	Intron 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK2	ENST00000262545.7	c.238A>G	p.Arg80Gly	missense_variant	Exon 2 of 12	1	NM_002594.5	ENSP00000262545.2
PCSK2	ENST00000377899.5	c.181A>G	p.Arg61Gly	missense_variant	Exon 3 of 13	1		ENSP00000367131.1
PCSK2	ENST00000536609.1	c.177+32818A>G		intron_variant	Intron 1 of 10	2		ENSP00000437458.1
PCSK2	ENST00000470007.1	n.233A>G		non_coding_transcript_exon_variant	Exon 2 of 6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251226 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135784

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461692 Hom.: 1 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.238A>G (p.R80G) alteration is located in exon 2 (coding exon 2) of the PCSK2 gene. This alteration results from a A to G substitution at nucleotide position 238, causing the arginine (R) at amino acid position 80 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	.;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.8	.;L
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.11
Sift	Benign	0.16	T;T
Sift4G	Benign	0.095	T;T
Polyphen		0.0	.;B
Vest4		0.66
MutPred		0.41		.;Loss of stability (P = 0.0078);
MVP		0.17
MPC		0.20
ClinPred		0.58	D
GERP RS		5.6
Varity_R		0.24
gMVP		0.77

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: rs1267879920; hg19: chr20-17240945;