chr19-44946027-T-G

Position:

• chr19-44946027-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NR_037932.1(APOC4-APOC2):​n.1146T>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.596 in 151,920 control chromosomes in the GnomAD database, including 28,108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (28079 hom., cov: 30)
  • Exomes 𝑓: 0.53 (29 hom.)
• Consequence: APOC4-APOC2 NR_037932.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.226

Genes affected

APOC4-APOC2 (HGNC:):

APOC2 (HGNC:609): (apolipoprotein C2) This gene encodes a lipid-binding protein belonging to the apolipoprotein gene family. The protein is secreted in plasma where it is a component of very low density lipoprotein. This protein activates the enzyme lipoprotein lipase, which hydrolyzes triglycerides and thus provides free fatty acids for cells. Mutations in this gene cause hyperlipoproteinemia type IB, characterized by hypertriglyceridemia, xanthomas, and increased risk of pancreatitis and early atherosclerosis. This gene is present in a cluster with other related apolipoprotein genes on chromosome 19. Naturally occurring read-through transcription exists between this gene and the neighboring upstream apolipoprotein C-IV (APOC4) gene. [provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 19-44946027-T-G is Benign according to our data. Variant chr19-44946027-T-G is described in ClinVar as [Benign]. Clinvar id is 329451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOC4-APOC2	NR_037932.1	n.1146T>G		non_coding_transcript_exon_variant	3/6
APOC2	NM_000483.5			upstream_gene_variant		ENST00000252490.7	NP_000474.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOC2	ENST00000252490.7			upstream_gene_variant		2	NM_000483.5	ENSP00000252490	P1
APOC2	ENST00000591597.5			upstream_gene_variant		5		ENSP00000476835
APOC2	ENST00000592257.5			upstream_gene_variant		3		ENSP00000477261

Frequencies

GnomAD3 genomes AF: 0.596 AC: 90352 AN: 151570 Hom.: 28035 Cov.: 30

Gnomad AFR AF: 0.744

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.672

Gnomad ASJ AF: 0.477

Gnomad EAS AF: 0.653

Gnomad SAS AF: 0.640

Gnomad FIN AF: 0.523

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.573

GnomAD4 exome AF: 0.526 AC: 122 AN: 232 Hom.: 29 Cov.: 0 AF XY: 0.522 AC XY: 96 AN XY: 184

Gnomad4 AFR exome AF: 1.00

Gnomad4 AMR exome AF: 0.500

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.583

Gnomad4 FIN exome AF: 0.286

Gnomad4 NFE exome AF: 0.522

Gnomad4 OTH exome AF: 0.643

GnomAD4 genome AF: 0.596 AC: 90448 AN: 151688 Hom.: 28079 Cov.: 30 AF XY: 0.598 AC XY: 44305 AN XY: 74066

Gnomad4 AFR AF: 0.745

Gnomad4 AMR AF: 0.673

Gnomad4 ASJ AF: 0.477

Gnomad4 EAS AF: 0.653

Gnomad4 SAS AF: 0.638

Gnomad4 FIN AF: 0.523

Gnomad4 NFE AF: 0.501

Gnomad4 OTH AF: 0.573

Alfa AF: 0.528 Hom.: 21621

Bravo AF: 0.614

Asia WGS AF: 0.667 AC: 2319 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial apolipoprotein C-II deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	8.9
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs2288911; hg19: chr19-45449284;