19-44948479-A-G

Position:

• chr19-44948479-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000483.5(APOC2):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APOC2 NM_000483.5 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 3.52

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:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-44948479-A-G is Pathogenic according to our data. Variant chr19-44948479-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 2579.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOC2	NM_000483.5	c.1A>G	p.Met1?	start_lost	2/4	ENST00000252490.7	NP_000474.2
APOC4-APOC2	NR_037932.1	n.1208A>G		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOC2	ENST00000252490.7	c.1A>G	p.Met1?	start_lost	2/4	2	NM_000483.5	ENSP00000252490	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461650 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727144

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Familial apolipoprotein C-II deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 15, 1989

- -

APOLIPOPROTEIN C-II (PARIS) Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 15, 1989

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.060	T;T;.;T;T;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.025
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.23	T;D;.;D;.;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Uncertain	0.51	D
MutationTaster	Benign	1.0	A;A;A
PROVEAN	Uncertain	-3.3	.;D;.;.;.;.
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	.;D;.;.;.;.
Sift4G	Uncertain	0.035	D;D;.;D;D;D
Polyphen		0.96	.;P;.;.;P;.
Vest4		0.88
MutPred		0.94		.;Gain of methylation at R4 (P = 0.1191);Gain of methylation at R4 (P = 0.1191);Gain of methylation at R4 (P = 0.1191);Gain of methylation at R4 (P = 0.1191);Gain of methylation at R4 (P = 0.1191);
MVP		0.64
ClinPred		0.97	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.80
gMVP		0.66

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: rs120074112; hg19: chr19-45451736;