chr19-44948512-G-A

Position:

• chr19-44948512-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_000483.5(APOC2):​c.34G>A​(p.Val12Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000295 in 1,614,130 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: APOC2 NM_000483.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.914

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 Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0075594783).
• BP6: Variant 19-44948512-G-A is Benign according to our data. Variant chr19-44948512-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1530932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-44948512-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000584 (89/152274) while in subpopulation AMR AF= 0.000981 (15/15294). AF 95% confidence interval is 0.000664. There are 0 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOC2	NM_000483.5	c.34G>A	p.Val12Ile	missense_variant	2/4	ENST00000252490.7	NP_000474.2
APOC4-APOC2	NR_037932.1	n.1241G>A		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOC2	ENST00000252490.7	c.34G>A	p.Val12Ile	missense_variant	2/4	2	NM_000483.5	ENSP00000252490	P1

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152156 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000346 AC: 87 AN: 251484 Hom.: 0 AF XY: 0.000361 AC XY: 49 AN XY: 135916

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000265 AC: 387 AN: 1461856 Hom.: 1 Cov.: 32 AF XY: 0.000254 AC XY: 185 AN XY: 727232

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000170

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152274 Hom.: 0 Cov.: 31 AF XY: 0.000685 AC XY: 51 AN XY: 74446

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000420 Hom.: 1

Bravo AF: 0.000669

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.056
DANN	Benign	0.73
DEOGEN2	Benign	0.013	T;T;.;T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.63	T;T;.;T;.;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.0076	T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.64	.;N;.;.;N;.
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-0.50	.;N;.;.;.;.
REVEL	Benign	0.090
Sift	Benign	0.40	.;T;.;.;.;.
Sift4G	Benign	0.33	T;T;.;T;T;T
Polyphen		0.0090	.;B;.;.;B;.
Vest4		0.088
MVP		0.16
MPC		0.15
ClinPred		0.0056	T
GERP RS		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.023
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs150887575; hg19: chr19-45451769;