1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_174936.4(PCSK9):​c.1503+70_1503+71delGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,502,512 control chromosomes in the GnomAD database, including 122 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (62 hom., cov: 0)
  • Exomes 𝑓: 0.015 (60 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.18
• 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant 1-55058666-CGT-C is Benign according to our data. Variant chr1-55058666-CGT-C is described in ClinVar as Benign. ClinVar VariationId is 928569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 62 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174936.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	NM_174936.4	MANE Select	c.1503+70_1503+71delGT		intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.1626+70_1626+71delGT		intron	N/A	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.1503+70_1503+71delGT		intron	N/A	NP_001394170.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.1503+20_1503+21delGT		intron	N/A	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.1860+20_1860+21delGT		intron	N/A	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.1626+20_1626+21delGT		intron	N/A	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.0294 AC: 4173 AN: 142008 Hom.: 62 Cov.: 0

Gnomad AFR AF: 0.0256

Gnomad AMI AF: 0.0102

Gnomad AMR AF: 0.0271

Gnomad ASJ AF: 0.0355

Gnomad EAS AF: 0.00189

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.0154

Gnomad MID AF: 0.0405

Gnomad NFE AF: 0.0371

Gnomad OTH AF: 0.0273

GnomAD2 exomes AF: 0.0127 AC: 1901 AN: 149146 AF XY: 0.0121

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.0160

Gnomad ASJ exome AF: 0.0153

Gnomad EAS exome AF: 0.00162

Gnomad FIN exome AF: 0.00392

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.0180

GnomAD4 exome AF: 0.0148 AC: 20128 AN: 1360424 Hom.: 60 AF XY: 0.0150 AC XY: 10143 AN XY: 674716

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

African (AFR) AF: 0.0160 AC: 495 AN: 30890

American (AMR) AF: 0.0134 AC: 522 AN: 38834

Ashkenazi Jewish (ASJ) AF: 0.0214 AC: 520 AN: 24316

East Asian (EAS) AF: 0.00497 AC: 183 AN: 36834

South Asian (SAS) AF: 0.0109 AC: 873 AN: 79954

European-Finnish (FIN) AF: 0.0153 AC: 721 AN: 47266

Middle Eastern (MID) AF: 0.0127 AC: 50 AN: 3952

European-Non Finnish (NFE) AF: 0.0151 AC: 15733 AN: 1042144

Other (OTH) AF: 0.0183 AC: 1031 AN: 56234

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0294 AC: 4179 AN: 142088 Hom.: 62 Cov.: 0 AF XY: 0.0277 AC XY: 1910 AN XY: 68838

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

African (AFR) AF: 0.0256 AC: 968 AN: 37784

American (AMR) AF: 0.0271 AC: 395 AN: 14556

Ashkenazi Jewish (ASJ) AF: 0.0355 AC: 119 AN: 3352

East Asian (EAS) AF: 0.00190 AC: 9 AN: 4740

South Asian (SAS) AF: 0.0140 AC: 61 AN: 4362

European-Finnish (FIN) AF: 0.0154 AC: 141 AN: 9134

Middle Eastern (MID) AF: 0.0331 AC: 9 AN: 272

European-Non Finnish (NFE) AF: 0.0371 AC: 2415 AN: 65052

Other (OTH) AF: 0.0271 AC: 53 AN: 1956

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0217 Hom.: 1122

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hypercholesterolemia, autosomal dominant, 3 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs35115360; hg19: chr1-55524339;