1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Position:

• chr1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 1568200.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-55058666-CGTGTGTGT-C is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 523 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1503+64_1503+71delGTGTGTGT		intron_variant		ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.1503+20_1503+27delGTGTGTGT		intron_variant		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

Gnomad4 AFR exome AF: 0.0104

Gnomad4 AMR exome AF: 0.000860

Gnomad4 ASJ exome AF: 0.000684

Gnomad4 EAS exome AF: 0.000270

Gnomad4 SAS exome AF: 0.000160

Gnomad4 FIN exome AF: 0.000479

Gnomad4 NFE exome AF: 0.000566

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.00367 AC: 523 AN: 142506 Hom.: 5 Cov.: 0 AF XY: 0.00345 AC XY: 238 AN XY: 69042

Gnomad4 AFR AF: 0.0126

Gnomad4 AMR AF: 0.000616

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000219

Gnomad4 NFE AF: 0.000505

Gnomad4 OTH AF: 0.000511

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs35115360; hg19: chr1-55524339;