chr15-101388220-T-G

Variant names:

• chr15-101388220-T-G
• rs3825904
• NM_002570.5:c.1310+1244A>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.1310+1244A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.622 in 152,188 control chromosomes in the GnomAD database, including 30,609 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 0.62 (30609 hom., cov: 34)
• Consequence: PCSK6 NM_002570.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.258
• Publications: 5 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=-0.55).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.717 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK6	NM_002570.5	c.1310+1244A>C		intron_variant	Intron 9 of 21	ENST00000611716.5	NP_002561.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK6	ENST00000611716.5	c.1310+1244A>C		intron_variant	Intron 9 of 21	1	NM_002570.5	ENSP00000482760.1

Frequencies

GnomAD3 genomes AF: 0.622 AC: 94648 AN: 152070 Hom.: 30590 Cov.: 34

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.783

Gnomad AMR AF: 0.728

Gnomad ASJ AF: 0.593

Gnomad EAS AF: 0.544

Gnomad SAS AF: 0.631

Gnomad FIN AF: 0.693

Gnomad MID AF: 0.621

Gnomad NFE AF: 0.708

Gnomad OTH AF: 0.654

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

GnomAD4 genome AF: 0.622 AC: 94702 AN: 152188 Hom.: 30609 Cov.: 34 AF XY: 0.622 AC XY: 46303 AN XY: 74406

African (AFR) AF: 0.431 AC: 17889 AN: 41508

American (AMR) AF: 0.728 AC: 11133 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.593 AC: 2057 AN: 3470

East Asian (EAS) AF: 0.544 AC: 2815 AN: 5178

South Asian (SAS) AF: 0.633 AC: 3055 AN: 4828

European-Finnish (FIN) AF: 0.693 AC: 7341 AN: 10596

Middle Eastern (MID) AF: 0.634 AC: 185 AN: 292

European-Non Finnish (NFE) AF: 0.708 AC: 48132 AN: 68008

Other (OTH) AF: 0.654 AC: 1381 AN: 2112

Alfa AF: 0.676 Hom.: 40496

Bravo AF: 0.616

Asia WGS AF: 0.591 AC: 2058 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.3
DANN	Benign	0.84
PhyloP100		0.26
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: rs3825904; hg19: chr15-101928425;