NM_002570.5:c.1858+16846T>C

Variant names:

• chr15-101349350-A-G
• rs11630183
• NM_002570.5:c.1858+16846T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002570.5(PCSK6):​c.1858+16846T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 152,208 control chromosomes in the GnomAD database, including 6,348 homozygotes. 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 0.26 (6348 hom., cov: 33)
• Consequence: PCSK6 NM_002570.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.302
• Publications: 4 publications found

Genes affected

PCSK6 (HGNC:8569): (proprotein convertase subtilisin/kexin type 6) 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 encoded protein undergoes an initial autocatalytic processing event in the ER to generate a heterodimer which exits the ER and sorts to the trans-Golgi network where a second autocatalytic event takes place and the catalytic activity is acquired. The encoded protease is constitutively secreted into the extracellular matrix and expressed in many tissues, including neuroendocrine, liver, gut, and brain. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. Some of its substrates include transforming growth factor beta related proteins, proalbumin, and von Willebrand factor. This gene is thought to play a role in tumor progression and left-right patterning. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Feb 2014]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK6	NM_002570.5	c.1858+16846T>C		intron_variant	Intron 13 of 21	ENST00000611716.5	NP_002561.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK6	ENST00000611716.5	c.1858+16846T>C		intron_variant	Intron 13 of 21	1	NM_002570.5	ENSP00000482760.1

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39326 AN: 152090 Hom.: 6334 Cov.: 33

Gnomad AFR AF: 0.456

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.242

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

GnomAD4 genome AF: 0.259 AC: 39392 AN: 152208 Hom.: 6348 Cov.: 33 AF XY: 0.255 AC XY: 19015 AN XY: 74424

African (AFR) AF: 0.456 AC: 18927 AN: 41498

American (AMR) AF: 0.224 AC: 3429 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 783 AN: 3470

East Asian (EAS) AF: 0.309 AC: 1597 AN: 5174

South Asian (SAS) AF: 0.104 AC: 504 AN: 4828

European-Finnish (FIN) AF: 0.183 AC: 1945 AN: 10610

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11511 AN: 68014

Other (OTH) AF: 0.247 AC: 521 AN: 2108

Alfa AF: 0.197 Hom.: 6003

Bravo AF: 0.274

Asia WGS AF: 0.250 AC: 869 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.1
DANN	Benign	0.83
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs11630183; hg19: chr15-101889555;