rs6232

Variant names:

• chr5-96416081-T-C
• rs6232
• NM_000439.5:c.661A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-96416081-T-C
• chr5-96416081-T-A
• chr5-96416081-T-G

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.661A>G​(p.Asn221Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0451 in 1,612,350 control chromosomes in the GnomAD database, including 1,870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (103 hom., cov: 33)
  • Exomes 𝑓: 0.046 (1767 hom.)
• Consequence: PCSK1 NM_000439.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 5.67
• Publications: 103 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=0.012222022).
• BP6: Variant 5-96416081-T-C is Benign according to our data. Variant chr5-96416081-T-C is described in ClinVar as Benign. ClinVar VariationId is 14040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0649 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.661A>G	p.Asn221Asp	missense	Exon 6 of 14	NP_000430.3
	PCSK1	NM_001177875.2		c.520A>G	p.Asn174Asp	missense	Exon 6 of 14	NP_001171346.1	P29120-2
	CAST	NM_001423250.1		c.-175+36429T>C		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.661A>G	p.Asn221Asp	missense	Exon 6 of 14	ENSP00000308024.2	P29120-1
	PCSK1	ENST00000947120.1		c.661A>G	p.Asn221Asp	missense	Exon 6 of 14	ENSP00000617179.1
	PCSK1	ENST00000914384.1		c.550A>G	p.Asn184Asp	missense	Exon 5 of 13	ENSP00000584443.1

Frequencies

GnomAD3 genomes AF: 0.0322 AC: 4909 AN: 152228 Hom.: 105 Cov.: 33

Gnomad AFR AF: 0.00924

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0274

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0522

Gnomad FIN AF: 0.0247

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0499

Gnomad OTH AF: 0.0296

GnomAD2 exomes AF: 0.0386 AC: 9706 AN: 251438 AF XY: 0.0420

Gnomad AFR exome AF: 0.00818

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.0173

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0309

Gnomad NFE exome AF: 0.0525

Gnomad OTH exome AF: 0.0370

GnomAD4 exome AF: 0.0465 AC: 67823 AN: 1460004 Hom.: 1767 Cov.: 29 AF XY: 0.0472 AC XY: 34289 AN XY: 726458

African (AFR) AF: 0.00792 AC: 265 AN: 33468

American (AMR) AF: 0.0164 AC: 735 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0169 AC: 442 AN: 26122

East Asian (EAS) AF: 0.000479 AC: 19 AN: 39678

South Asian (SAS) AF: 0.0663 AC: 5718 AN: 86218

European-Finnish (FIN) AF: 0.0336 AC: 1796 AN: 53404

Middle Eastern (MID) AF: 0.0533 AC: 307 AN: 5762

European-Non Finnish (NFE) AF: 0.0506 AC: 56193 AN: 1110294

Other (OTH) AF: 0.0389 AC: 2348 AN: 60338

GnomAD4 genome AF: 0.0322 AC: 4903 AN: 152346 Hom.: 103 Cov.: 33 AF XY: 0.0313 AC XY: 2331 AN XY: 74496

African (AFR) AF: 0.00921 AC: 383 AN: 41580

American (AMR) AF: 0.0274 AC: 419 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3472

East Asian (EAS) AF: 0.00173 AC: 9 AN: 5190

South Asian (SAS) AF: 0.0514 AC: 248 AN: 4826

European-Finnish (FIN) AF: 0.0247 AC: 262 AN: 10622

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0499 AC: 3395 AN: 68032

Other (OTH) AF: 0.0298 AC: 63 AN: 2114

Alfa AF: 0.0456 Hom.: 813

Bravo AF: 0.0316

TwinsUK AF: 0.0496 AC: 184

ALSPAC AF: 0.0589 AC: 227

ESP6500AA AF: 0.00999 AC: 44

ESP6500EA AF: 0.0501 AC: 431

ExAC AF: 0.0399 AC: 4842

Asia WGS AF: 0.0210 AC: 73 AN: 3478

EpiCase AF: 0.0505

EpiControl AF: 0.0507

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	-	Body mass index quantitative trait locus 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.3	L
PhyloP100		5.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.45
Sift	Benign	0.12	T
Sift4G	Benign	0.19	T
Polyphen		0.036	B
Vest4		0.080
MPC		0.30
ClinPred		0.031	T
GERP RS		6.1
Varity_R		0.61
gMVP		0.76
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs6232; hg19: chr5-95751785; COSMIC: COSV60736739; COSMIC: COSV60736739;