19-44948399-T-G

Variant names:

• chr19-44948399-T-G
• rs10422603
• NM_000483.5:c.-13-67T>G

Variant summary

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

The NM_000483.5(APOC2):​c.-13-67T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 1,349,646 control chromosomes in the GnomAD database, including 27,614 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3749 hom., cov: 31)
  • Exomes 𝑓: 0.19 (23865 hom.)
• Consequence: APOC2 NM_000483.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.39
• Publications: 11 publications found

Genes affected

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]

APOC4-APOC2 (HGNC:44426): (APOC4-APOC2 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring apolipoprotein C-IV (APOC4) and apolipoprotein C-II (APOC2) genes on chromosome 19. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Mar 2011]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-44948399-T-G is Benign according to our data. Variant chr19-44948399-T-G is described in ClinVar as Benign. ClinVar VariationId is 1255025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.302 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOC2	NM_000483.5	c.-13-67T>G		intron_variant	Intron 1 of 3	ENST00000252490.7	NP_000474.2
APOC4-APOC2	NR_037932.1	n.1195-67T>G		intron_variant	Intron 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOC2	ENST00000252490.7	c.-13-67T>G		intron_variant	Intron 1 of 3	2	NM_000483.5	ENSP00000252490.5
APOC4-APOC2	ENST00000589057.5	c.219-67T>G		intron_variant	Intron 2 of 4	5		ENSP00000468139.1

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32211 AN: 151376 Hom.: 3747 Cov.: 31

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.0864

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.184

GnomAD4 exome AF: 0.191 AC: 229135 AN: 1198152 Hom.: 23865 Cov.: 17 AF XY: 0.195 AC XY: 118663 AN XY: 608428

African (AFR) AF: 0.295 AC: 8226 AN: 27858

American (AMR) AF: 0.230 AC: 10151 AN: 44174

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 3995 AN: 24510

East Asian (EAS) AF: 0.0696 AC: 2677 AN: 38456

South Asian (SAS) AF: 0.316 AC: 25472 AN: 80610

European-Finnish (FIN) AF: 0.158 AC: 8391 AN: 53074

Middle Eastern (MID) AF: 0.192 AC: 1010 AN: 5254

European-Non Finnish (NFE) AF: 0.182 AC: 159014 AN: 872394

Other (OTH) AF: 0.197 AC: 10199 AN: 51822

GnomAD4 genome AF: 0.213 AC: 32234 AN: 151494 Hom.: 3749 Cov.: 31 AF XY: 0.211 AC XY: 15647 AN XY: 74002

African (AFR) AF: 0.292 AC: 12054 AN: 41272

American (AMR) AF: 0.204 AC: 3107 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 548 AN: 3468

East Asian (EAS) AF: 0.0859 AC: 441 AN: 5136

South Asian (SAS) AF: 0.315 AC: 1507 AN: 4786

European-Finnish (FIN) AF: 0.148 AC: 1558 AN: 10536

Middle Eastern (MID) AF: 0.137 AC: 40 AN: 292

European-Non Finnish (NFE) AF: 0.182 AC: 12346 AN: 67804

Other (OTH) AF: 0.181 AC: 380 AN: 2098

Alfa AF: 0.201 Hom.: 432

Bravo AF: 0.218

Asia WGS AF: 0.200 AC: 698 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aug 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.26
DANN	Benign	0.64
PhyloP100		-1.4
PromoterAI		0.034	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs10422603; hg19: chr19-45451656; COSMIC: COSV52990219; COSMIC: COSV52990219;