15-101305277-G-A

Position:

• chr15-101305277-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.2891C>T​(p.Thr964Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00419 in 1,611,692 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (18 hom.)
• Consequence: PCSK6 NM_002570.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.86

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]

SNRPA1-DT (HGNC:55431): (SNRPA1 divergent transcript)

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015419096).
• BP6: Variant 15-101305277-G-A is Benign according to our data. Variant chr15-101305277-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 788742.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.2891C>T	p.Thr964Met	missense_variant	22/22	ENST00000611716.5
SNRPA1-DT	XR_007064783.1	n.8798G>A		non_coding_transcript_exon_variant	2/2
PCSK6	NM_138319.4	c.2852C>T	p.Thr951Met	missense_variant	21/21
PCSK6	NM_001291309.2	c.2669C>T	p.Thr890Met	missense_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK6	ENST00000611716.5	c.2891C>T	p.Thr964Met	missense_variant	22/22	1	NM_002570.5	A2
SNRPA1-DT	ENST00000558838.1	n.2130G>A		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 451 AN: 152210 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00504

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00321 AC: 788 AN: 245790 Hom.: 1 AF XY: 0.00336 AC XY: 449 AN XY: 133824

Gnomad AFR exome AF: 0.000395

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00270

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00158

Gnomad FIN exome AF: 0.00490

Gnomad NFE exome AF: 0.00488

Gnomad OTH exome AF: 0.00334

GnomAD4 exome AF: 0.00432 AC: 6308 AN: 1459364 Hom.: 18 Cov.: 30 AF XY: 0.00438 AC XY: 3180 AN XY: 725982

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00241

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00170

Gnomad4 FIN exome AF: 0.00511

Gnomad4 NFE exome AF: 0.00500

Gnomad4 OTH exome AF: 0.00318

GnomAD4 genome AF: 0.00295 AC: 450 AN: 152328 Hom.: 2 Cov.: 32 AF XY: 0.00267 AC XY: 199 AN XY: 74486

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.00504

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00429 Hom.: 3

Bravo AF: 0.00284

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.000472 AC: 2

ESP6500EA AF: 0.00461 AC: 39

ExAC AF: 0.00334 AC: 404

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00463

EpiControl AF: 0.00463

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	Sep 20, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T;T;.;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.015	T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.2	M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.9	.;D;.;.
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	.;D;.;.
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.58
MVP		0.80
ClinPred		0.012	T
GERP RS		5.0
Varity_R		0.29
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs34631529; hg19: chr15-101845482;