rs7552350

Variant names:

• chr1-55052525-C-A
• rs7552350
• NM_174936.4:c.657+114C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-55052525-C-A
• chr1-55052525-C-G
• chr1-55052525-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_174936.4(PCSK9):​c.657+114C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,535,416 control chromosomes in the GnomAD database, including 19,261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2147 hom., cov: 34)
  • Exomes 𝑓: 0.16 (17114 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00500
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-55052525-C-A is Benign according to our data. Variant chr1-55052525-C-A is described in ClinVar as Benign. ClinVar VariationId is 265929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	NM_174936.4	MANE Select	c.657+114C>A		intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.780+114C>A		intron	N/A	NP_001394169.1
	PCSK9	NM_001407241.1		c.657+114C>A		intron	N/A	NP_001394170.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.657+114C>A		intron	N/A	ENSP00000303208.5
	PCSK9	ENST00000710286.1		c.1014+114C>A		intron	N/A	ENSP00000518176.1
	PCSK9	ENST00000713786.1		c.780+114C>A		intron	N/A	ENSP00000519088.1

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24575 AN: 150374 Hom.: 2142 Cov.: 34

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.0496

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0880

Gnomad MID AF: 0.148

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.171

GnomAD4 exome AF: 0.157 AC: 217594 AN: 1384924 Hom.: 17114 Cov.: 36 AF XY: 0.157 AC XY: 107935 AN XY: 688098

African (AFR) AF: 0.214 AC: 7066 AN: 32996

American (AMR) AF: 0.103 AC: 4368 AN: 42214

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 4562 AN: 24930

East Asian (EAS) AF: 0.0400 AC: 1539 AN: 38436

South Asian (SAS) AF: 0.121 AC: 9906 AN: 81964

European-Finnish (FIN) AF: 0.0922 AC: 4567 AN: 49530

Middle Eastern (MID) AF: 0.157 AC: 844 AN: 5390

European-Non Finnish (NFE) AF: 0.167 AC: 175895 AN: 1051646

Other (OTH) AF: 0.153 AC: 8847 AN: 57818

GnomAD4 genome AF: 0.163 AC: 24599 AN: 150492 Hom.: 2147 Cov.: 34 AF XY: 0.157 AC XY: 11539 AN XY: 73358

African (AFR) AF: 0.204 AC: 8421 AN: 41356

American (AMR) AF: 0.142 AC: 2143 AN: 15058

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 603 AN: 3452

East Asian (EAS) AF: 0.0497 AC: 249 AN: 5010

South Asian (SAS) AF: 0.107 AC: 508 AN: 4738

European-Finnish (FIN) AF: 0.0880 AC: 906 AN: 10298

Middle Eastern (MID) AF: 0.156 AC: 45 AN: 288

European-Non Finnish (NFE) AF: 0.165 AC: 11090 AN: 67286

Other (OTH) AF: 0.169 AC: 355 AN: 2102

Alfa AF: 0.180 Hom.: 569

Bravo AF: 0.168

Asia WGS AF: 0.0860 AC: 300 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hypercholesterolemia, familial, 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.2
DANN	Benign	0.78
PhyloP100		0.0050
Mutation Taster		=14/86	disease causing

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: rs7552350; hg19: chr1-55518198; COSMIC: COSV56162577;