rs2483205

Variant names:

• chr1-55052643-C-T
• rs2483205
• NM_174936.4:c.658-7C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-55052643-C-T
• chr1-55052643-C-A

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.658-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 1,612,178 control chromosomes in the GnomAD database, including 154,963 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (15442 hom., cov: 34)
  • Exomes 𝑓: 0.43 (139521 hom.)
• Consequence: PCSK9 NM_174936.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001414
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:19
• Conservation: PhyloP100: -0.272
• Publications: 36 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-55052643-C-T is Benign according to our data. Variant chr1-55052643-C-T is described in ClinVar as Benign. ClinVar VariationId is 36672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.484 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	NM_174936.4	MANE Select	c.658-7C>T		splice_region intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.781-7C>T		splice_region intron	N/A	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.658-7C>T		splice_region 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.658-7C>T		splice_region intron	N/A	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.1015-7C>T		splice_region intron	N/A	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.781-7C>T		splice_region intron	N/A	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.446 AC: 67804 AN: 152030 Hom.: 15440 Cov.: 34

Gnomad AFR AF: 0.490

Gnomad AMI AF: 0.600

Gnomad AMR AF: 0.378

Gnomad ASJ AF: 0.495

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.433

GnomAD2 exomes AF: 0.419 AC: 104152 AN: 248680 AF XY: 0.425

Gnomad AFR exome AF: 0.489

Gnomad AMR exome AF: 0.319

Gnomad ASJ exome AF: 0.501

Gnomad EAS exome AF: 0.218

Gnomad FIN exome AF: 0.463

Gnomad NFE exome AF: 0.449

Gnomad OTH exome AF: 0.421

GnomAD4 exome AF: 0.434 AC: 634366 AN: 1460030 Hom.: 139521 Cov.: 72 AF XY: 0.436 AC XY: 316773 AN XY: 726170

African (AFR) AF: 0.496 AC: 16593 AN: 33466

American (AMR) AF: 0.323 AC: 14447 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.506 AC: 13196 AN: 26094

East Asian (EAS) AF: 0.234 AC: 9289 AN: 39678

South Asian (SAS) AF: 0.446 AC: 38460 AN: 86180

European-Finnish (FIN) AF: 0.454 AC: 23882 AN: 52614

Middle Eastern (MID) AF: 0.465 AC: 2683 AN: 5766

European-Non Finnish (NFE) AF: 0.441 AC: 489957 AN: 1111220

Other (OTH) AF: 0.429 AC: 25859 AN: 60332

GnomAD4 genome AF: 0.446 AC: 67847 AN: 152148 Hom.: 15442 Cov.: 34 AF XY: 0.444 AC XY: 33048 AN XY: 74392

African (AFR) AF: 0.490 AC: 20322 AN: 41512

American (AMR) AF: 0.378 AC: 5783 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 1717 AN: 3472

East Asian (EAS) AF: 0.223 AC: 1152 AN: 5158

South Asian (SAS) AF: 0.430 AC: 2076 AN: 4826

European-Finnish (FIN) AF: 0.468 AC: 4961 AN: 10602

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.445 AC: 30224 AN: 67972

Other (OTH) AF: 0.430 AC: 908 AN: 2110

Alfa AF: 0.447 Hom.: 43619

Bravo AF: 0.439

Asia WGS AF: 0.337 AC: 1177 AN: 3478

EpiCase AF: 0.455

EpiControl AF: 0.456

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Hypercholesterolemia, familial, 1 (5)
-	-	5	not specified (5)
-	-	4	Hypercholesterolemia, autosomal dominant, 3 (4)
-	-	2	Familial hypercholesterolemia (2)
-	-	2	not provided (2)
-	-	1	Hypobetalipoproteinemia (1)
-	1	-	Short fetal femur length (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.56
PhyloP100		-0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
SpliceAI score (max)		0.010		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: rs2483205; hg19: chr1-55518316; COSMIC: COSV56162583;