1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant names:

• chr1-55058666-C-CGTGTGTGTGTGT
• rs35115360
• NM_174936.4:c.1503+60_1503+71dupGTGTGTGTGTGT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_174936.4(PCSK9):​c.1503+60_1503+71dupGTGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000042 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.20
• 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 -2 ACMG points.

• BP6: Variant 1-55058666-C-CGTGTGTGTGTGT is Benign according to our data. Variant chr1-55058666-C-CGTGTGTGTGTGT is described in ClinVar as Likely_benign. ClinVar VariationId is 3673014.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1503+60_1503+71dupGTGTGTGTGTGT		intron_variant	Intron 9 of 11	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.1503+19_1503+20insGTGTGTGTGTGT		intron_variant	Intron 9 of 11	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.0000421 AC: 6 AN: 142438 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000919

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000108 AC: 15 AN: 1392898 Hom.: 0 Cov.: 0 AF XY: 0.0000145 AC XY: 10 AN XY: 690652

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000316 AC: 1 AN: 31628

American (AMR) AF: 0.00 AC: 0 AN: 39552

Ashkenazi Jewish (ASJ) AF: 0.0000402 AC: 1 AN: 24880

East Asian (EAS) AF: 0.00 AC: 0 AN: 36988

South Asian (SAS) AF: 0.00 AC: 0 AN: 81354

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4014

European-Non Finnish (NFE) AF: 0.0000112 AC: 12 AN: 1068930

Other (OTH) AF: 0.0000174 AC: 1 AN: 57564

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000421 AC: 6 AN: 142438 Hom.: 0 Cov.: 0 AF XY: 0.0000725 AC XY: 5 AN XY: 68950

African (AFR) AF: 0.00 AC: 0 AN: 37766

American (AMR) AF: 0.00 AC: 0 AN: 14588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3364

East Asian (EAS) AF: 0.00 AC: 0 AN: 4752

South Asian (SAS) AF: 0.00 AC: 0 AN: 4378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 296

European-Non Finnish (NFE) AF: 0.0000919 AC: 6 AN: 65318

Other (OTH) AF: 0.00 AC: 0 AN: 1944

Alfa AF: 0.00 Hom.: 1122

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Benign:1

Aug 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35115360; hg19: chr1-55524339;