1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant names:

• chr1-55058666-CGTGTGT-C
• rs35115360
• NM_174936.4:c.1503+66_1503+71delGTGTGT

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+66_1503+71delGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,532,782 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 0)
  • Exomes 𝑓: 0.0018 (1 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.181
• 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-CGTGTGT-C is Benign according to our data. Variant chr1-55058666-CGTGTGT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1579070.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00251 (357/142500) while in subpopulation AFR AF = 0.00486 (184/37856). AF 95% confidence interval is 0.00429. There are 2 homozygotes in GnomAd4. There are 168 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1503+66_1503+71delGTGTGT		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+25delGTGTGT		intron_variant	Intron 9 of 11	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 353 AN: 142420 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00477

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00158

Gnomad ASJ AF: 0.00654

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000228

Gnomad FIN AF: 0.00240

Gnomad MID AF: 0.00338

Gnomad NFE AF: 0.00149

Gnomad OTH AF: 0.00360

GnomAD4 exome AF: 0.00178 AC: 2477 AN: 1390282 Hom.: 1 AF XY: 0.00173 AC XY: 1196 AN XY: 689396

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

African (AFR) AF: 0.00616 AC: 194 AN: 31492

American (AMR) AF: 0.00121 AC: 48 AN: 39514

Ashkenazi Jewish (ASJ) AF: 0.00480 AC: 119 AN: 24804

East Asian (EAS) AF: 0.000189 AC: 7 AN: 36982

South Asian (SAS) AF: 0.000640 AC: 52 AN: 81298

European-Finnish (FIN) AF: 0.00402 AC: 192 AN: 47812

Middle Eastern (MID) AF: 0.00174 AC: 7 AN: 4012

European-Non Finnish (NFE) AF: 0.00163 AC: 1737 AN: 1066896

Other (OTH) AF: 0.00211 AC: 121 AN: 57472

⚠️ 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: 0.00251 AC: 357 AN: 142500 Hom.: 2 Cov.: 0 AF XY: 0.00243 AC XY: 168 AN XY: 69038

African (AFR) AF: 0.00486 AC: 184 AN: 37856

American (AMR) AF: 0.00158 AC: 23 AN: 14602

Ashkenazi Jewish (ASJ) AF: 0.00654 AC: 22 AN: 3364

East Asian (EAS) AF: 0.00 AC: 0 AN: 4740

South Asian (SAS) AF: 0.000229 AC: 1 AN: 4372

European-Finnish (FIN) AF: 0.00240 AC: 22 AN: 9148

Middle Eastern (MID) AF: 0.00368 AC: 1 AN: 272

European-Non Finnish (NFE) AF: 0.00149 AC: 97 AN: 65308

Other (OTH) AF: 0.00358 AC: 7 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 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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		0.18
Mutation Taster		=100/0	polymorphism

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;