rs139453594

Variant names:

• chr5-96393345-T-C
• rs139453594
• NM_000439.5:c.1918A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000439.5(PCSK1):​c.1918A>G​(p.Thr640Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,614,020 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T640T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (4 hom.)
• Consequence: PCSK1 NM_000439.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5
• Conservation: PhyloP100: -1.67
• Publications: 12 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, Orphanet, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp

CAST (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048470795).
• BP6: Variant 5-96393345-T-C is Benign according to our data. Variant chr5-96393345-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436278.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00159 (242/152198) while in subpopulation AMR AF = 0.00471 (72/15296). AF 95% confidence interval is 0.00383. There are 0 homozygotes in GnomAd4. There are 106 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK1	NM_000439.5	MANE Select	c.1918A>G	p.Thr640Ala	missense	Exon 14 of 14	NP_000430.3
	PCSK1	NM_001177875.2		c.1777A>G	p.Thr593Ala	missense	Exon 14 of 14	NP_001171346.1
	CAST	NM_001423250.1		c.-175+13693T>C		intron	N/A	NP_001410179.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK1	ENST00000311106.8	TSL:1 MANE Select	c.1918A>G	p.Thr640Ala	missense	Exon 14 of 14	ENSP00000308024.2
	PCSK1	ENST00000513085.1	TSL:1	n.1061A>G		non_coding_transcript_exon	Exon 8 of 8
	PCSK1	ENST00000508626.5	TSL:2	c.1777A>G	p.Thr593Ala	missense	Exon 14 of 14	ENSP00000421600.1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 243 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00197

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00135 AC: 339 AN: 250328 AF XY: 0.00130

Gnomad AFR exome AF: 0.000576

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.00457

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00180

Gnomad OTH exome AF: 0.00279

GnomAD4 exome AF: 0.00235 AC: 3432 AN: 1461822 Hom.: 4 Cov.: 33 AF XY: 0.00223 AC XY: 1622 AN XY: 727210

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.00204 AC: 91 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00440 AC: 115 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53412

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5754

European-Non Finnish (NFE) AF: 0.00271 AC: 3008 AN: 1111974

Other (OTH) AF: 0.00326 AC: 197 AN: 60394

GnomAD4 genome AF: 0.00159 AC: 242 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.00142 AC XY: 106 AN XY: 74408

African (AFR) AF: 0.000385 AC: 16 AN: 41506

American (AMR) AF: 0.00471 AC: 72 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00197 AC: 134 AN: 68006

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00189 Hom.: 1

Bravo AF: 0.00227

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00119 AC: 145

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	3	-	Obesity due to prohormone convertase I deficiency (3)
-	1	1	not specified (2)
-	1	-	PCSK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.072
DANN	Benign	0.39
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N
PhyloP100		-1.7
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.026
Sift	Benign	0.76	T
Sift4G	Benign	0.84	T
Polyphen		0.0	B
Vest4		0.0090
MVP		0.43
MPC		0.26
ClinPred		0.0012	T
GERP RS		-3.7
Varity_R		0.016
gMVP		0.41
Mutation Taster		=98/2	polymorphism

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: rs139453594; hg19: chr5-95729049;