1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant names:

• chr1-55058666-C-CGT
• rs35115360
• NM_174936.4:c.1503+70_1503+71dupGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_174936.4(PCSK9):​c.1503+70_1503+71dupGT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (30 hom., cov: 0)
  • Exomes 𝑓: 0.0045 (4 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 1-55058666-C-CGT is Benign according to our data. Variant chr1-55058666-C-CGT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 928570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0187 (2662/142256) while in subpopulation SAS AF = 0.0232 (101/4362). AF 95% confidence interval is 0.0215. There are 30 homozygotes in GnomAd4. There are 1228 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1503+70_1503+71dupGT		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+20insGT		intron_variant	Intron 9 of 11	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2658 AN: 142178 Hom.: 30 Cov.: 0

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.00341

Gnomad AMR AF: 0.00961

Gnomad ASJ AF: 0.0295

Gnomad EAS AF: 0.000631

Gnomad SAS AF: 0.0227

Gnomad FIN AF: 0.00733

Gnomad MID AF: 0.0203

Gnomad NFE AF: 0.0208

Gnomad OTH AF: 0.0149

GnomAD4 exome AF: 0.00453 AC: 6264 AN: 1382268 Hom.: 4 Cov.: 0 AF XY: 0.00479 AC XY: 3282 AN XY: 685196

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

African (AFR) AF: 0.00741 AC: 232 AN: 31330

American (AMR) AF: 0.00408 AC: 161 AN: 39454

Ashkenazi Jewish (ASJ) AF: 0.00962 AC: 237 AN: 24634

East Asian (EAS) AF: 0.00157 AC: 58 AN: 36960

South Asian (SAS) AF: 0.00986 AC: 793 AN: 80390

European-Finnish (FIN) AF: 0.00350 AC: 167 AN: 47764

Middle Eastern (MID) AF: 0.00626 AC: 25 AN: 3992

European-Non Finnish (NFE) AF: 0.00400 AC: 4246 AN: 1060666

Other (OTH) AF: 0.00604 AC: 345 AN: 57078

⚠️ 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: 0.0187 AC: 2662 AN: 142256 Hom.: 30 Cov.: 0 AF XY: 0.0178 AC XY: 1228 AN XY: 68908

African (AFR) AF: 0.0228 AC: 859 AN: 37748

American (AMR) AF: 0.00960 AC: 140 AN: 14582

Ashkenazi Jewish (ASJ) AF: 0.0295 AC: 99 AN: 3352

East Asian (EAS) AF: 0.000633 AC: 3 AN: 4740

South Asian (SAS) AF: 0.0232 AC: 101 AN: 4362

European-Finnish (FIN) AF: 0.00733 AC: 67 AN: 9138

Middle Eastern (MID) AF: 0.0221 AC: 6 AN: 272

European-Non Finnish (NFE) AF: 0.0208 AC: 1355 AN: 65224

Other (OTH) AF: 0.0148 AC: 29 AN: 1958

Alfa AF: 0.0178 Hom.: 1122

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Feb 10, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PCSK9 c.1503+70_1503+71dupGT is located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0059 in 1524524 control chromosomes, predominantly at a frequency of 0.016 within the African or African-American subpopulation in the gnomAD database, including 10 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 426.66 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (3.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.1503+70_1503+71dupGT in individuals affected with Familial Hypercholesterolemia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 928570). Based on the evidence outlined above, the variant was classified as benign. -

Hypercholesterolemia, autosomal dominant, 3 Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Nov 13, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.2
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;