NM_174936.4:c.-64C>T

Variant names:

• chr1-55039774-C-T
• rs45448095
• NM_174936.4:c.-64C>T

Variant summary

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

The NM_174936.4(PCSK9):​c.-64C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,546,470 control chromosomes in the GnomAD database, including 14,642 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.098 (901 hom., cov: 34)
  • Exomes 𝑓: 0.14 (13741 hom.)
• Consequence: PCSK9 NM_174936.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.546
• Publications: 18 publications found

Genes affected

PCSK9 (HGNC:20001): (proprotein convertase subtilisin/kexin type 9) 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 autocatalytic processing event with its prosegment in the ER and is constitutively secreted as an inactive protease into the extracellular matrix and trans-Golgi network. It is expressed in liver, intestine and kidney tissues and escorts specific receptors for lysosomal degradation. It plays a role in cholesterol and fatty acid metabolism. Mutations in this gene have been associated with autosomal dominant familial hypercholesterolemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

PCSK9 Gene-Disease associations (from GenCC):

• hypercholesterolemia, autosomal dominant, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-55039774-C-T is Benign according to our data. Variant chr1-55039774-C-T is described in ClinVar as Benign. ClinVar VariationId is 36666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.-64C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 12	ENST00000302118.5	NP_777596.2
PCSK9	NM_174936.4	c.-64C>T		5_prime_UTR_variant	Exon 1 of 12	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.-64C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 12	1	NM_174936.4	ENSP00000303208.5
PCSK9	ENST00000302118.5	c.-64C>T		5_prime_UTR_variant	Exon 1 of 12	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.0982 AC: 14951 AN: 152222 Hom.: 896 Cov.: 34

Gnomad AFR AF: 0.0247

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.0826

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.0865

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.107

GnomAD4 exome AF: 0.137 AC: 190480 AN: 1394130 Hom.: 13741 Cov.: 27 AF XY: 0.137 AC XY: 94782 AN XY: 689374

African (AFR) AF: 0.0197 AC: 639 AN: 32442

American (AMR) AF: 0.0706 AC: 2615 AN: 37056

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 3960 AN: 25078

East Asian (EAS) AF: 0.127 AC: 4772 AN: 37534

South Asian (SAS) AF: 0.150 AC: 11926 AN: 79732

European-Finnish (FIN) AF: 0.0958 AC: 4687 AN: 48908

Middle Eastern (MID) AF: 0.107 AC: 433 AN: 4052

European-Non Finnish (NFE) AF: 0.144 AC: 154157 AN: 1071526

Other (OTH) AF: 0.126 AC: 7291 AN: 57802

GnomAD4 genome AF: 0.0981 AC: 14947 AN: 152340 Hom.: 901 Cov.: 34 AF XY: 0.0958 AC XY: 7133 AN XY: 74496

African (AFR) AF: 0.0246 AC: 1025 AN: 41600

American (AMR) AF: 0.0824 AC: 1261 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 559 AN: 3470

East Asian (EAS) AF: 0.116 AC: 600 AN: 5176

South Asian (SAS) AF: 0.150 AC: 724 AN: 4830

European-Finnish (FIN) AF: 0.0865 AC: 919 AN: 10620

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9335 AN: 68022

Other (OTH) AF: 0.108 AC: 229 AN: 2114

Alfa AF: 0.108 Hom.: 119

Bravo AF: 0.0972

Asia WGS AF: 0.130 AC: 451 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:2

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypercholesterolemia, autosomal dominant, 3 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hypobetalipoproteinemia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.3
DANN	Benign	0.91
PhyloP100		-0.55
PromoterAI		-0.061	Neutral
Mutation Taster		=300/0	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: rs45448095; hg19: chr1-55505447; COSMIC: COSV56162238;