rs271921

Positions:

• chr5-96401410-T-A
• chr5-96401410-T-C
• chr5-96401410-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000439.5(PCSK1):​c.1197-1224A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: PCSK1 NM_000439.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.335

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK1	NM_000439.5	c.1197-1224A>T		intron_variant		ENST00000311106.8	NP_000430.3
LOC101929710	NR_130776.1	n.354+21758T>A		intron_variant, non_coding_transcript_variant
PCSK1	NM_001177875.2	c.1056-1224A>T		intron_variant			NP_001171346.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK1	ENST00000311106.8	c.1197-1224A>T		intron_variant		1	NM_000439.5	ENSP00000308024	P1
	ENST00000502645.2	n.354+21758T>A		intron_variant, non_coding_transcript_variant		5
PCSK1	ENST00000513085.1	n.340-1224A>T		intron_variant, non_coding_transcript_variant		1
PCSK1	ENST00000508626.5	c.1056-1224A>T		intron_variant		2		ENSP00000421600

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.8
DANN	Benign	0.71

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: rs271921; hg19: chr5-95737114;