chr19-44948277-T-G

Variant names:

• chr19-44948277-T-G
• rs12721060
• NM_000483.5:c.-13-189T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000483.5(APOC2):​c.-13-189T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 599,928 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00088 (2 hom.)
• Consequence: APOC2 NM_000483.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.20
• Publications: 2 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=-0.79).
• BP6: Variant 19-44948277-T-G is Benign according to our data. Variant chr19-44948277-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1254202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00572 (863/150800) while in subpopulation AFR AF = 0.0196 (805/41026). AF 95% confidence interval is 0.0185. There are 9 homozygotes in GnomAd4. There are 416 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000483.5. 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
	APOC2	NM_000483.5	MANE Select	c.-13-189T>G		intron	N/A	NP_000474.2
	APOC4-APOC2	NR_037932.1		n.1195-189T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOC2	ENST00000252490.7	TSL:2 MANE Select	c.-13-189T>G		intron	N/A	ENSP00000252490.5	P02655
	APOC4-APOC2	ENST00000589057.5	TSL:5	c.219-189T>G		intron	N/A	ENSP00000468139.1	K7ER74
	APOC2	ENST00000896559.1		c.-202T>G		5_prime_UTR	Exon 3 of 5	ENSP00000566618.1

Frequencies

GnomAD3 genomes AF: 0.00569 AC: 857 AN: 150684 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00218

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000637

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000163

Gnomad OTH AF: 0.00532

GnomAD4 exome AF: 0.000877 AC: 394 AN: 449128 Hom.: 2 Cov.: 3 AF XY: 0.000812 AC XY: 194 AN XY: 239008

African (AFR) AF: 0.0197 AC: 238 AN: 12078

American (AMR) AF: 0.00149 AC: 29 AN: 19406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14338

East Asian (EAS) AF: 0.0000341 AC: 1 AN: 29320

South Asian (SAS) AF: 0.000386 AC: 18 AN: 46668

European-Finnish (FIN) AF: 0.0000294 AC: 1 AN: 34052

Middle Eastern (MID) AF: 0.00204 AC: 4 AN: 1956

European-Non Finnish (NFE) AF: 0.000188 AC: 50 AN: 265924

Other (OTH) AF: 0.00209 AC: 53 AN: 25386

GnomAD4 genome AF: 0.00572 AC: 863 AN: 150800 Hom.: 9 Cov.: 33 AF XY: 0.00565 AC XY: 416 AN XY: 73612

African (AFR) AF: 0.0196 AC: 805 AN: 41026

American (AMR) AF: 0.00218 AC: 33 AN: 15124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.000638 AC: 3 AN: 4704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000163 AC: 11 AN: 67582

Other (OTH) AF: 0.00526 AC: 11 AN: 2090

Alfa AF: 0.00437 Hom.: 2

Bravo AF: 0.00646

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.0
DANN	Benign	0.85
PhyloP100		-1.2
PromoterAI		0.0073	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs12721060; hg19: chr19-45451534;