rs1018736752

Positions:

• chr18-2934416-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001375808.2(LPIN2):​c.1203T>G​(p.Asp401Glu) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D401H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LPIN2 NM_001375808.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.206

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0780772).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPIN2	NM_001375808.2	c.1203T>G	p.Asp401Glu	missense_variant	8/20	ENST00000677752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPIN2	ENST00000677752.1	c.1203T>G	p.Asp401Glu	missense_variant	8/20		NM_001375808.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000548 AC: 80 AN: 1459424 Hom.: 0 Cov.: 30 AF XY: 0.0000427 AC XY: 31 AN XY: 726134

Gnomad4 AFR exome AF: 0.0000599

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: 0.0000667

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Majeed syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 18, 2022

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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 536349). 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 aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 401 of the LPIN2 protein (p.Asp401Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	2.4
DANN	Uncertain	0.99
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.75	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.33
Sift	Benign	0.17	T
Sift4G	Benign	0.60	T
Polyphen		0.0080	B
Vest4		0.14
MutPred		0.083		Gain of MoRF binding (P = 0.2218);
MVP		0.30
MPC		0.22
ClinPred		0.24	T
GERP RS		-0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.076

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: rs1018736752; hg19: chr18-2934414;