1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGT

Position:

• chr1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGT

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+62_1503+71delGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0084 (27 hom., cov: 0)
  • Exomes 𝑓: 0.0021 (7 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: 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-CGTGTGTGTGT-C is Benign according to our data. Variant chr1-55058666-CGTGTGTGTGT-C is described in ClinVar as [Benign]. Clinvar id is 1598662.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-55058666-CGTGTGTGTGT-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00843 (1201/142496) while in subpopulation AFR AF= 0.0258 (977/37854). AF 95% confidence interval is 0.0245. There are 27 homozygotes in gnomad4. There are 538 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1201 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1503+62_1503+71delGTGTGTGTGT		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+29delGTGTGTGTGT		intron_variant		1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.00838 AC: 1194 AN: 142416 Hom.: 27 Cov.: 0

Gnomad AFR AF: 0.0257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00446

Gnomad ASJ AF: 0.00238

Gnomad EAS AF: 0.00400

Gnomad SAS AF: 0.00320

Gnomad FIN AF: 0.000328

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00159

Gnomad OTH AF: 0.00566

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00206 AC: 2864 AN: 1392040 Hom.: 7 AF XY: 0.00197 AC XY: 1359 AN XY: 690178

Gnomad4 AFR exome AF: 0.0246

Gnomad4 AMR exome AF: 0.00405

Gnomad4 ASJ exome AF: 0.00169

Gnomad4 EAS exome AF: 0.00287

Gnomad4 SAS exome AF: 0.00182

Gnomad4 FIN exome AF: 0.000855

Gnomad4 NFE exome AF: 0.00128

Gnomad4 OTH exome AF: 0.00363

GnomAD4 genome AF: 0.00843 AC: 1201 AN: 142496 Hom.: 27 Cov.: 0 AF XY: 0.00779 AC XY: 538 AN XY: 69036

Gnomad4 AFR AF: 0.0258

Gnomad4 AMR AF: 0.00445

Gnomad4 ASJ AF: 0.00238

Gnomad4 EAS AF: 0.00401

Gnomad4 SAS AF: 0.00320

Gnomad4 FIN AF: 0.000328

Gnomad4 NFE AF: 0.00159

Gnomad4 OTH AF: 0.00562

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 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;