15-101325267-T-C

Variant names:

• chr15-101325267-T-C
• rs7182874
• NM_002570.5:c.2181-221A>G

Variant summary

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

The NM_002570.5(PCSK6):​c.2181-221A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.714 in 152,102 control chromosomes in the GnomAD database, including 38,990 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 0.71 (38990 hom., cov: 32)
• Consequence: PCSK6 NM_002570.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.300
• Publications: 9 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]

PCSK6 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.796 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002570.5. 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
	PCSK6	NM_002570.5	MANE Select	c.2181-221A>G		intron	N/A	NP_002561.1	P29122-1
	PCSK6	NM_138319.4		c.2142-221A>G		intron	N/A	NP_612192.1	P29122-2
	PCSK6	NM_001291309.2		c.1959-221A>G		intron	N/A	NP_001278238.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK6	ENST00000611716.5	TSL:1 MANE Select	c.2181-221A>G		intron	N/A	ENSP00000482760.1	P29122-1
	PCSK6	ENST00000622483.4	TSL:1	c.2181-221A>G		intron	N/A	ENSP00000481556.1	A0A087WY68
	PCSK6	ENST00000619160.4	TSL:1	c.2142-221A>G		intron	N/A	ENSP00000482831.1	A0A087WZR0

Frequencies

GnomAD3 genomes AF: 0.714 AC: 108520 AN: 151984 Hom.: 38948 Cov.: 32

Gnomad AFR AF: 0.716

Gnomad AMI AF: 0.833

Gnomad AMR AF: 0.786

Gnomad ASJ AF: 0.639

Gnomad EAS AF: 0.816

Gnomad SAS AF: 0.477

Gnomad FIN AF: 0.703

Gnomad MID AF: 0.704

Gnomad NFE AF: 0.709

Gnomad OTH AF: 0.730

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

GnomAD4 genome AF: 0.714 AC: 108615 AN: 152102 Hom.: 38990 Cov.: 32 AF XY: 0.711 AC XY: 52870 AN XY: 74352

African (AFR) AF: 0.716 AC: 29702 AN: 41488

American (AMR) AF: 0.786 AC: 12021 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.639 AC: 2218 AN: 3472

East Asian (EAS) AF: 0.816 AC: 4224 AN: 5174

South Asian (SAS) AF: 0.478 AC: 2298 AN: 4812

European-Finnish (FIN) AF: 0.703 AC: 7440 AN: 10576

Middle Eastern (MID) AF: 0.712 AC: 208 AN: 292

European-Non Finnish (NFE) AF: 0.709 AC: 48206 AN: 67980

Other (OTH) AF: 0.730 AC: 1538 AN: 2106

Alfa AF: 0.712 Hom.: 60243

Bravo AF: 0.731

Asia WGS AF: 0.656 AC: 2281 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.1
DANN	Benign	0.59
PhyloP100		-0.30
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: rs7182874; hg19: chr15-101865472;