20-17335297-C-T

Variant names:

• chr20-17335297-C-T
• rs6044739
• NM_002594.5:c.283-23030C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002594.5(PCSK2):​c.283-23030C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.596 in 143,250 control chromosomes in the GnomAD database, including 26,824 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.60 (26824 hom., cov: 23)
• Consequence: PCSK2 NM_002594.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.99
• Publications: 3 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK2	NM_002594.5	c.283-23030C>T		intron_variant	Intron 2 of 11	ENST00000262545.7	NP_002585.2
PCSK2	NM_001201528.2	c.226-23030C>T		intron_variant	Intron 3 of 12		NP_001188457.1
PCSK2	NM_001201529.3	c.178-23030C>T		intron_variant	Intron 1 of 10		NP_001188458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK2	ENST00000262545.7	c.283-23030C>T		intron_variant	Intron 2 of 11	1	NM_002594.5	ENSP00000262545.2
PCSK2	ENST00000377899.5	c.226-23030C>T		intron_variant	Intron 3 of 12	1		ENSP00000367131.1
PCSK2	ENST00000536609.1	c.178-23030C>T		intron_variant	Intron 1 of 10	2		ENSP00000437458.1
PCSK2	ENST00000470007.1	n.278-23030C>T		intron_variant	Intron 2 of 5	3

Frequencies

GnomAD3 genomes AF: 0.597 AC: 85377 AN: 143128 Hom.: 26805 Cov.: 23

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.698

Gnomad ASJ AF: 0.694

Gnomad EAS AF: 0.966

Gnomad SAS AF: 0.704

Gnomad FIN AF: 0.648

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.637

Gnomad OTH AF: 0.607

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.596 AC: 85433 AN: 143250 Hom.: 26824 Cov.: 23 AF XY: 0.600 AC XY: 41570 AN XY: 69316

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

African (AFR) AF: 0.420 AC: 16470 AN: 39206

American (AMR) AF: 0.699 AC: 9812 AN: 14038

Ashkenazi Jewish (ASJ) AF: 0.694 AC: 2323 AN: 3346

East Asian (EAS) AF: 0.967 AC: 4464 AN: 4618

South Asian (SAS) AF: 0.703 AC: 2995 AN: 4262

European-Finnish (FIN) AF: 0.648 AC: 6100 AN: 9420

Middle Eastern (MID) AF: 0.591 AC: 162 AN: 274

European-Non Finnish (NFE) AF: 0.637 AC: 41537 AN: 65254

Other (OTH) AF: 0.609 AC: 1186 AN: 1946

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.636 Hom.: 131256

Bravo AF: 0.604

Asia WGS AF: 0.790 AC: 2746 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.013
DANN	Benign	0.20
PhyloP100		-3.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs6044739; hg19: chr20-17315942;