chr1-55058666-CGTGTGTGT-C

Variant names:

• chr1-55058666-CGTGTGTGT-C
• rs35115360
• NM_174936.4:c.1503+64_1503+71delGTGTGTGT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_174936.4(PCSK9):​c.1503+64_1503+71delGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,534,792 control chromosomes in the GnomAD database, including 10 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0037 (5 hom., cov: 0)
  • Exomes 𝑓: 0.00079 (5 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.564
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-55058666-CGTGTGTGT-C is Benign according to our data. Variant chr1-55058666-CGTGTGTGT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1568200.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00367 (523/142506) while in subpopulation AFR AF = 0.0126 (478/37860). AF 95% confidence interval is 0.0117. There are 5 homozygotes in GnomAd4. There are 238 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1503+64_1503+71delGTGTGTGT		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+20_1503+27delGTGTGTGT		intron_variant	Intron 9 of 11	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 520 AN: 142426 Hom.: 5 Cov.: 0

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000617

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000219

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000505

Gnomad OTH AF: 0.000514

GnomAD4 exome AF: 0.000792 AC: 1102 AN: 1392286 Hom.: 5 AF XY: 0.000701 AC XY: 484 AN XY: 690340

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

African (AFR) AF: 0.0104 AC: 328 AN: 31530

American (AMR) AF: 0.000860 AC: 34 AN: 39548

Ashkenazi Jewish (ASJ) AF: 0.000684 AC: 17 AN: 24858

East Asian (EAS) AF: 0.000270 AC: 10 AN: 36984

South Asian (SAS) AF: 0.000160 AC: 13 AN: 81342

European-Finnish (FIN) AF: 0.000479 AC: 23 AN: 47974

Middle Eastern (MID) AF: 0.00125 AC: 5 AN: 4014

European-Non Finnish (NFE) AF: 0.000566 AC: 605 AN: 1068504

Other (OTH) AF: 0.00116 AC: 67 AN: 57532

⚠️ 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: 0.00367 AC: 523 AN: 142506 Hom.: 5 Cov.: 0 AF XY: 0.00345 AC XY: 238 AN XY: 69042

African (AFR) AF: 0.0126 AC: 478 AN: 37860

American (AMR) AF: 0.000616 AC: 9 AN: 14604

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4738

South Asian (SAS) AF: 0.00 AC: 0 AN: 4372

European-Finnish (FIN) AF: 0.000219 AC: 2 AN: 9150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.000505 AC: 33 AN: 65308

Other (OTH) AF: 0.000511 AC: 1 AN: 1958

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

Jan 20, 2025

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		0.56

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;