NM_002594.5:c.1430+11delG

Variant names:

• chr20-17465559-TG-T
• rs140522302
• NM_002594.5:c.1430+11delG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_002594.5(PCSK2):​c.1430+11delG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,543,892 control chromosomes in the GnomAD database, including 180 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (95 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (85 hom.)
• Consequence: PCSK2 NM_002594.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.07
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 20-17465559-TG-T is Benign according to our data. Variant chr20-17465559-TG-T is described in ClinVar as Benign. ClinVar VariationId is 777519.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0634 is higher than 0.05.

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.1430+11delG		intron	N/A	NP_002585.2
	PCSK2	NM_001201528.2		c.1373+11delG		intron	N/A	NP_001188457.1	P16519-3
	PCSK2	NM_001201529.3		c.1325+11delG		intron	N/A	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.1430+7delG		splice_region intron	N/A	ENSP00000262545.2	P16519-1
	PCSK2	ENST00000377899.5	TSL:1	c.1373+7delG		splice_region intron	N/A	ENSP00000367131.1	P16519-3
	PCSK2	ENST00000947703.1		c.1427+7delG		splice_region intron	N/A	ENSP00000617762.1

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2859 AN: 152162 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.0654

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.00549 AC: 1176 AN: 214050 AF XY: 0.00374

Gnomad AFR exome AF: 0.0671

Gnomad AMR exome AF: 0.00368

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.00332

GnomAD4 exome AF: 0.00191 AC: 2652 AN: 1391612 Hom.: 85 Cov.: 24 AF XY: 0.00160 AC XY: 1102 AN XY: 687258

African (AFR) AF: 0.0628 AC: 2008 AN: 31954

American (AMR) AF: 0.00419 AC: 170 AN: 40540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22952

East Asian (EAS) AF: 0.00 AC: 0 AN: 39042

South Asian (SAS) AF: 0.0000511 AC: 4 AN: 78208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51706

Middle Eastern (MID) AF: 0.00296 AC: 16 AN: 5414

European-Non Finnish (NFE) AF: 0.000202 AC: 215 AN: 1064240

Other (OTH) AF: 0.00415 AC: 239 AN: 57556

GnomAD4 genome AF: 0.0188 AC: 2866 AN: 152280 Hom.: 95 Cov.: 32 AF XY: 0.0174 AC XY: 1297 AN XY: 74464

African (AFR) AF: 0.0654 AC: 2717 AN: 41536

American (AMR) AF: 0.00588 AC: 90 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68022

Other (OTH) AF: 0.0175 AC: 37 AN: 2116

Alfa AF: 0.0105 Hom.: 8

Bravo AF: 0.0213

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs140522302; hg19: chr20-17446204;