5-96397408-A-G

Variant names:

• chr5-96397408-A-G
• rs6233
• NM_000439.5:c.1650T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000439.5(PCSK1):​c.1650T>C​(p.Asn550Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 1,610,164 control chromosomes in the GnomAD database, including 112,577 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11019 hom., cov: 32)
  • Exomes 𝑓: 0.37 (101558 hom.)
• Consequence: PCSK1 NM_000439.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.23
• Publications: 25 publications found

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]

CAST (HGNC:1515): (calpastatin) The protein encoded by this gene is an endogenous calpain (calcium-dependent cysteine protease) inhibitor. It consists of an N-terminal domain L and four repetitive calpain-inhibition domains (domains 1-4), and it is involved in the proteolysis of amyloid precursor protein. The calpain/calpastatin system is involved in numerous membrane fusion events, such as neural vesicle exocytosis and platelet and red-cell aggregation. The encoded protein is also thought to affect the expression levels of genes encoding structural or regulatory proteins. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2010]

CAST Gene-Disease associations (from GenCC):

• peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

CAST (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 5-96397408-A-G is Benign according to our data. Variant chr5-96397408-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 354643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000439.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK1	NM_000439.5	MANE Select	c.1650T>C	p.Asn550Asn	synonymous	Exon 12 of 14	NP_000430.3
	PCSK1	NM_001177875.2		c.1509T>C	p.Asn503Asn	synonymous	Exon 12 of 14	NP_001171346.1	P29120-2
	CAST	NM_001423250.1		c.-175+17756A>G		intron	N/A	NP_001410179.1	P20810-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK1	ENST00000311106.8	TSL:1 MANE Select	c.1650T>C	p.Asn550Asn	synonymous	Exon 12 of 14	ENSP00000308024.2	P29120-1
	PCSK1	ENST00000513085.1	TSL:1	n.793T>C		non_coding_transcript_exon	Exon 6 of 8
	PCSK1	ENST00000947120.1		c.1650T>C	p.Asn550Asn	synonymous	Exon 12 of 14	ENSP00000617179.1

Frequencies

GnomAD3 genomes AF: 0.376 AC: 57070 AN: 151892 Hom.: 11014 Cov.: 32

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.447

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.397

GnomAD2 exomes AF: 0.358 AC: 89902 AN: 251166 AF XY: 0.352

Gnomad AFR exome AF: 0.417

Gnomad AMR exome AF: 0.468

Gnomad ASJ exome AF: 0.426

Gnomad EAS exome AF: 0.268

Gnomad FIN exome AF: 0.218

Gnomad NFE exome AF: 0.368

Gnomad OTH exome AF: 0.365

GnomAD4 exome AF: 0.370 AC: 538956 AN: 1458154 Hom.: 101558 Cov.: 30 AF XY: 0.368 AC XY: 266682 AN XY: 725638

African (AFR) AF: 0.419 AC: 14009 AN: 33398

American (AMR) AF: 0.458 AC: 20487 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 10771 AN: 26102

East Asian (EAS) AF: 0.299 AC: 11845 AN: 39650

South Asian (SAS) AF: 0.297 AC: 25617 AN: 86176

European-Finnish (FIN) AF: 0.225 AC: 12040 AN: 53404

Middle Eastern (MID) AF: 0.425 AC: 2449 AN: 5760

European-Non Finnish (NFE) AF: 0.378 AC: 419370 AN: 1108686

Other (OTH) AF: 0.371 AC: 22368 AN: 60262

GnomAD4 genome AF: 0.376 AC: 57101 AN: 152010 Hom.: 11019 Cov.: 32 AF XY: 0.371 AC XY: 27570 AN XY: 74300

African (AFR) AF: 0.417 AC: 17282 AN: 41434

American (AMR) AF: 0.446 AC: 6811 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 1419 AN: 3466

East Asian (EAS) AF: 0.275 AC: 1423 AN: 5176

South Asian (SAS) AF: 0.282 AC: 1360 AN: 4816

European-Finnish (FIN) AF: 0.216 AC: 2289 AN: 10582

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.371 AC: 25230 AN: 67942

Other (OTH) AF: 0.401 AC: 848 AN: 2116

Alfa AF: 0.388 Hom.: 19441

Bravo AF: 0.395

Asia WGS AF: 0.280 AC: 978 AN: 3476

EpiCase AF: 0.383

EpiControl AF: 0.379

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Monogenic Non-Syndromic Obesity (1)
-	-	1	Obesity due to prohormone convertase I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	3.7
DANN	Benign	0.73
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6233; hg19: chr5-95733112; COSMIC: COSV60734130;