rs547662448

chr18-2920334-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001375808.2(LPIN2):c.2650C>T(p.Arg884Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,614,142 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: LPIN2 NM_001375808.2 stop_gained
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.95

Genes affected

LPIN2 (HGNC:14450): (lipin 2) Mouse studies suggest that this gene functions during normal adipose tissue development and may play a role in human triglyceride metabolism. This gene represents a candidate gene for human lipodystrophy, characterized by loss of body fat, fatty liver, hypertriglyceridemia, and insulin resistance. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0152 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPIN2	NM_001375808.2	c.2650C>T	p.Arg884Ter	stop_gained	20/20	ENST00000677752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPIN2	ENST00000677752.1	c.2650C>T	p.Arg884Ter	stop_gained	20/20		NM_001375808.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251298 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135890

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 48 AN: 1461812 Hom.: 0 Cov.: 33 AF XY: 0.0000426 AC XY: 31 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74496

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000422 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Majeed syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 15, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 01, 2022	This sequence change creates a premature translational stop signal (p.Arg884*) in the LPIN2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 13 amino acid(s) of the LPIN2 protein. This variant is present in population databases (rs547662448, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with LPIN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 234344). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 08, 2017

The R884X variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R884X nonsense variant results in the loss of the final 13 amino acids of the LPIN2 protein; however, no nonsense-mediated decay is predicted and no downstream loss of function variants have been reported to our knowledge. The variant is observed in 6/120838 (.00497%) alleles in the ExAC dataset (Lek et al., 2016). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	42
Dann	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.86	D
MutationTaster	Benign	1.0	D
Vest4		0.75
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs547662448; hg19: chr18-2920332;