chr15-101313475-G-A

Position:

• chr15-101313475-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002570.5(PCSK6):​c.2600C>T​(p.Ala867Val) variant causes a missense change. The variant allele was found at a frequency of 0.00314 in 1,609,260 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (11 hom.)
• Consequence: PCSK6 NM_002570.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.70

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

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069431663).
• BP6: Variant 15-101313475-G-A is Benign according to our data. Variant chr15-101313475-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 720144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK6	NM_002570.5	c.2600C>T	p.Ala867Val	missense_variant	20/22	ENST00000611716.5
PCSK6	NM_138319.4	c.2561C>T	p.Ala854Val	missense_variant	19/21
PCSK6	NM_001291309.2	c.2378C>T	p.Ala793Val	missense_variant	18/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK6	ENST00000611716.5	c.2600C>T	p.Ala867Val	missense_variant	20/22	1	NM_002570.5	A2

Frequencies

GnomAD3 genomes AF: 0.00247 AC: 376 AN: 152202 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00367

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00242 AC: 593 AN: 244672 Hom.: 0 AF XY: 0.00229 AC XY: 305 AN XY: 133342

Gnomad AFR exome AF: 0.000455

Gnomad AMR exome AF: 0.00270

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00406

Gnomad OTH exome AF: 0.00217

GnomAD4 exome AF: 0.00321 AC: 4681 AN: 1456940 Hom.: 11 Cov.: 31 AF XY: 0.00303 AC XY: 2194 AN XY: 724848

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00271

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00133

Gnomad4 NFE exome AF: 0.00389

Gnomad4 OTH exome AF: 0.00229

GnomAD4 genome AF: 0.00247 AC: 376 AN: 152320 Hom.: 2 Cov.: 33 AF XY: 0.00244 AC XY: 182 AN XY: 74480

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00470

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00368

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00248 Hom.: 0

Bravo AF: 0.00213

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00394 AC: 33

ExAC AF: 0.00262 AC: 317

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00326

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T;.;T;T;T
Eigen	Benign	0.064
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.84	T;T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0069	T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L;.;.;.;.;.
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	.;N;.;.;.;.
REVEL	Benign	0.19
Sift	Benign	0.21	.;T;.;.;.;.
Sift4G	Benign	0.18	T;T;T;T;T;T
Polyphen		0.036	B;.;.;.;.;.
Vest4		0.31
MVP		0.55
ClinPred		0.014	T
GERP RS		4.7
Varity_R		0.080
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs149680467; hg19: chr15-101853680; COSMIC: COSV61853759; COSMIC: COSV61853759;