rs6233

Positions:

• chr5-96397408-A-C
• chr5-96397408-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000311106.8(PCSK1):​c.1650T>G​(p.Asn550Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N550N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCSK1 ENST00000311106.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.23

Genes affected

PCSK1 (HGNC:8743): (proprotein convertase subtilisin/kexin type 1) 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 subcellular compartments where a second autocatalytic even takes place and the catalytic activity is acquired. The protease is packaged into and activated in dense core secretory granules and expressed in the neuroendocrine system and brain. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. It functions in the proteolytic activation of polypeptide hormones and neuropeptides precursors. Mutations in this gene have been associated with susceptibility to obesity and proprotein convertase 1/3 deficiency. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene [provided by RefSeq, Jan 2014]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK1	NM_000439.5	c.1650T>G	p.Asn550Lys	missense_variant	12/14	ENST00000311106.8	NP_000430.3
LOC101929710	NR_130776.1	n.354+17756A>C		intron_variant, non_coding_transcript_variant
PCSK1	NM_001177875.2	c.1509T>G	p.Asn503Lys	missense_variant	12/14		NP_001171346.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK1	ENST00000311106.8	c.1650T>G	p.Asn550Lys	missense_variant	12/14	1	NM_000439.5	ENSP00000308024	P1
PCSK1	ENST00000513085.1	n.793T>G		non_coding_transcript_exon_variant	6/8	1
	ENST00000502645.2	n.354+17756A>C		intron_variant, non_coding_transcript_variant		5
PCSK1	ENST00000508626.5	c.1509T>G	p.Asn503Lys	missense_variant	12/14	2		ENSP00000421600

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459522 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726268

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	10
DANN	Benign	0.97
DEOGEN2	Uncertain	0.70	D;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.77
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.73	N;.
MutationTaster	Benign	0.00077	P;P
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Benign	0.19
Sift	Benign	0.17	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.19	B;.
Vest4		0.62
MutPred		0.53		Gain of methylation at N550 (P = 0.0022);.;
MVP		0.51
MPC		0.38
ClinPred		0.30	T
GERP RS		-6.4
Varity_R		0.41
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6233; hg19: chr5-95733112;