NM_017573.5:c.1946G>T

Variant names:

• chr19-1482081-C-A
• rs78359732
• NM_017573.5:c.1946G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_017573.5(PCSK4):​c.1946G>T​(p.Cys649Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00946 in 1,552,464 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0054 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0099 (86 hom.)
• Consequence: PCSK4 NM_017573.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.832
• Publications: 9 publications found

Genes affected

PCSK4 (HGNC:8746): (proprotein convertase subtilisin/kexin type 4) 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. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. The protease is expressed only in the testis, placenta, and ovary. It plays a critical role in fertilization, fetoplacental growth, and embryonic development and processes multiple prohormones including pro-pituitary adenylate cyclase-activating protein and pro-insulin-like growth factor II. [provided by RefSeq, Jan 2014]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010106891).
• BP6: Variant 19-1482081-C-A is Benign according to our data. Variant chr19-1482081-C-A is described in ClinVar as Benign. ClinVar VariationId is 2648935.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 86 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017573.5. 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
	PCSK4	NM_017573.5	MANE Select	c.1946G>T	p.Cys649Phe	missense	Exon 15 of 15	NP_060043.2	Q6UW60-1
	PCSK4	NM_001395257.1		c.*120G>T		3_prime_UTR	Exon 14 of 14	NP_001382186.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK4	ENST00000300954.10	TSL:1 MANE Select	c.1946G>T	p.Cys649Phe	missense	Exon 15 of 15	ENSP00000300954.5	Q6UW60-1
	PCSK4	ENST00000883590.1		c.1919G>T	p.Cys640Phe	missense	Exon 15 of 15	ENSP00000553649.1
	PCSK4	ENST00000441747.6	TSL:2	n.1988G>T		non_coding_transcript_exon	Exon 12 of 12

Frequencies

GnomAD3 genomes AF: 0.00543 AC: 826 AN: 152184 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00991

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00474 AC: 704 AN: 148602 AF XY: 0.00463

Gnomad AFR exome AF: 0.00131

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.000121

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00259

Gnomad NFE exome AF: 0.00985

Gnomad OTH exome AF: 0.00577

GnomAD4 exome AF: 0.00990 AC: 13866 AN: 1400162 Hom.: 86 Cov.: 33 AF XY: 0.00966 AC XY: 6688 AN XY: 692098

African (AFR) AF: 0.00116 AC: 37 AN: 31884

American (AMR) AF: 0.00268 AC: 98 AN: 36596

Ashkenazi Jewish (ASJ) AF: 0.000674 AC: 17 AN: 25236

East Asian (EAS) AF: 0.00 AC: 0 AN: 36138

South Asian (SAS) AF: 0.000250 AC: 20 AN: 79996

European-Finnish (FIN) AF: 0.00270 AC: 115 AN: 42600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4844

European-Non Finnish (NFE) AF: 0.0120 AC: 13003 AN: 1084636

Other (OTH) AF: 0.00989 AC: 576 AN: 58232

GnomAD4 genome AF: 0.00542 AC: 826 AN: 152302 Hom.: 1 Cov.: 33 AF XY: 0.00475 AC XY: 354 AN XY: 74458

African (AFR) AF: 0.00171 AC: 71 AN: 41556

American (AMR) AF: 0.00261 AC: 40 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00282 AC: 30 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00991 AC: 674 AN: 67994

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00679 Hom.: 2

Bravo AF: 0.00547

ESP6500AA AF: 0.00101 AC: 4

ESP6500EA AF: 0.00852 AC: 67

ExAC AF: 0.00230 AC: 257

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.83
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.94	P
Vest4		0.55
MVP		0.60
MPC		0.79
ClinPred		0.098	T
GERP RS		2.8
Varity_R		0.72
gMVP		0.93
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs78359732; hg19: chr19-1482080;