chr1-55056196-GC-G

Variant names:

• chr1-55056196-GC-G
• rs768213924
• NM_174936.4:c.996+8delC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_174936.4(PCSK9):​c.996+8delC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,395,934 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: PCSK9 NM_174936.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 0.362
• Publications: 1 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 1-55056196-GC-G is Benign according to our data. Variant chr1-55056196-GC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 297698.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.996+8delC		splice_region_variant, intron_variant	Intron 6 of 11	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.996+8delC		splice_region_variant, intron_variant	Intron 6 of 11	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.000186 AC: 28 AN: 150330 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00780

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000354 AC: 24 AN: 67710 AF XY: 0.000335

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00947

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000757

Gnomad OTH exome AF: 0.000649

GnomAD4 exome AF: 0.000156 AC: 194 AN: 1245604 Hom.: 0 Cov.: 33 AF XY: 0.000156 AC XY: 94 AN XY: 602644

African (AFR) AF: 0.00 AC: 0 AN: 27412

American (AMR) AF: 0.00 AC: 0 AN: 23066

Ashkenazi Jewish (ASJ) AF: 0.00788 AC: 146 AN: 18534

East Asian (EAS) AF: 0.00 AC: 0 AN: 30760

South Asian (SAS) AF: 0.00 AC: 0 AN: 55470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3552

European-Non Finnish (NFE) AF: 0.0000231 AC: 23 AN: 995080

Other (OTH) AF: 0.000496 AC: 25 AN: 50372

GnomAD4 genome AF: 0.000186 AC: 28 AN: 150330 Hom.: 0 Cov.: 30 AF XY: 0.000164 AC XY: 12 AN XY: 73318

African (AFR) AF: 0.00 AC: 0 AN: 40824

American (AMR) AF: 0.00 AC: 0 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.00780 AC: 27 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5024

South Asian (SAS) AF: 0.00 AC: 0 AN: 4702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67454

Other (OTH) AF: 0.00 AC: 0 AN: 2048

Alfa AF: 0.000821 Hom.: 0

Bravo AF: 0.000215

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Apr 17, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PCSK9: BP4 -

Hypercholesterolemia, familial, 1 Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hypobetalipoproteinemia Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Oct 09, 2022

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

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PCSK9-related disorder Benign:1

Aug 12, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial hypercholesterolemia Benign:1

Jul 06, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36

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: rs768213924; hg19: chr1-55521869;