NM_000439.5:c.2069G>C

Variant names:

• chr5-96393194-C-G
• rs6235
• NM_000439.5:c.2069G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000439.5(PCSK1):​c.2069G>C​(p.Ser690Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 1,613,804 control chromosomes in the GnomAD database, including 57,039 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4376 hom., cov: 32)
  • Exomes 𝑓: 0.27 (52663 hom.)
• Consequence: PCSK1 NM_000439.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.04
• Publications: 145 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042052567).
• BP6: Variant 5-96393194-C-G is Benign according to our data. Variant chr5-96393194-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 354639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.296 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.2069G>C	p.Ser690Thr	missense	Exon 14 of 14	NP_000430.3
	PCSK1	NM_001177875.2		c.1928G>C	p.Ser643Thr	missense	Exon 14 of 14	NP_001171346.1	P29120-2
	CAST	NM_001423250.1		c.-175+13542C>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.2069G>C	p.Ser690Thr	missense	Exon 14 of 14	ENSP00000308024.2	P29120-1
	PCSK1	ENST00000513085.1	TSL:1	n.1212G>C		non_coding_transcript_exon	Exon 8 of 8
	PCSK1	ENST00000947120.1		c.2066G>C	p.Ser689Thr	missense	Exon 14 of 14	ENSP00000617179.1

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35319 AN: 151932 Hom.: 4381 Cov.: 32

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.247

GnomAD2 exomes AF: 0.263 AC: 66025 AN: 251426 AF XY: 0.268

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.198

Gnomad ASJ exome AF: 0.287

Gnomad EAS exome AF: 0.309

Gnomad FIN exome AF: 0.284

Gnomad NFE exome AF: 0.273

Gnomad OTH exome AF: 0.258

GnomAD4 exome AF: 0.266 AC: 389239 AN: 1461754 Hom.: 52663 Cov.: 35 AF XY: 0.268 AC XY: 194699 AN XY: 727184

African (AFR) AF: 0.146 AC: 4875 AN: 33478

American (AMR) AF: 0.197 AC: 8798 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 7647 AN: 26136

East Asian (EAS) AF: 0.264 AC: 10477 AN: 39700

South Asian (SAS) AF: 0.303 AC: 26166 AN: 86254

European-Finnish (FIN) AF: 0.285 AC: 15200 AN: 53418

Middle Eastern (MID) AF: 0.235 AC: 1356 AN: 5768

European-Non Finnish (NFE) AF: 0.269 AC: 298842 AN: 1111886

Other (OTH) AF: 0.263 AC: 15878 AN: 60392

GnomAD4 genome AF: 0.232 AC: 35311 AN: 152050 Hom.: 4376 Cov.: 32 AF XY: 0.232 AC XY: 17233 AN XY: 74306

African (AFR) AF: 0.155 AC: 6425 AN: 41496

American (AMR) AF: 0.202 AC: 3092 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 966 AN: 3466

East Asian (EAS) AF: 0.309 AC: 1589 AN: 5150

South Asian (SAS) AF: 0.308 AC: 1477 AN: 4800

European-Finnish (FIN) AF: 0.278 AC: 2931 AN: 10554

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.266 AC: 18100 AN: 67986

Other (OTH) AF: 0.246 AC: 520 AN: 2114

Alfa AF: 0.263 Hom.: 4040

Bravo AF: 0.227

TwinsUK AF: 0.272 AC: 1007

ALSPAC AF: 0.287 AC: 1107

ESP6500AA AF: 0.159 AC: 702

ESP6500EA AF: 0.278 AC: 2389

ExAC AF: 0.265 AC: 32196

Asia WGS AF: 0.278 AC: 967 AN: 3478

EpiCase AF: 0.268

EpiControl AF: 0.276

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	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
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		1.0
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.16
Sift	Benign	0.19	T
Sift4G	Benign	0.28	T
Polyphen		0.0010	B
Vest4		0.052
MPC		0.25
ClinPred		0.00042	T
GERP RS		4.0
Varity_R		0.11
gMVP		0.20
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6235; hg19: chr5-95728898; COSMIC: COSV60735309;