18-2920401-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001375808.2(LPIN2):​c.2583C>A​(p.Phe861Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

LPIN2
NM_001375808.2 missense

Scores

13
5
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.05
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LPIN2NM_001375808.2 linkc.2583C>A p.Phe861Leu missense_variant Exon 20 of 20 ENST00000677752.1 NP_001362737.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LPIN2ENST00000677752.1 linkc.2583C>A p.Phe861Leu missense_variant Exon 20 of 20 NM_001375808.2 ENSP00000504857.1 Q92539

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Majeed syndrome Uncertain:1
Apr 07, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals affected with LPIN2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 861 of the LPIN2 protein (p.Phe861Leu). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.47
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.58
D
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.57
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Pathogenic
3.4
M
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-5.2
D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.96
MutPred
0.83
Gain of catalytic residue at F861 (P = 0.0794);
MVP
0.92
MPC
0.94
ClinPred
1.0
D
GERP RS
1.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.86
gMVP
0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-2920399; API