18-2929105-G-A

Variant names:

• chr18-2929105-G-A
• rs104895500
• NM_001375808.2:c.1510C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001375808.2(LPIN2):​c.1510C>T​(p.Leu504Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0032 in 1,606,330 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (14 hom.)
• Consequence: LPIN2 NM_001375808.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:8 O:1
• Conservation: PhyloP100: 6.79
• Publications: 12 publications found

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]

LPIN2 Gene-Disease associations (from GenCC):

• Majeed syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016277522).
• BP6: Variant 18-2929105-G-A is Benign according to our data. Variant chr18-2929105-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97814.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00259 (395/152276) while in subpopulation NFE AF = 0.00416 (283/68016). AF 95% confidence interval is 0.00376. There are 2 homozygotes in GnomAd4. There are 172 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375808.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPIN2	NM_001375808.2	MANE Select	c.1510C>T	p.Leu504Phe	missense	Exon 10 of 20	NP_001362737.1
	LPIN2	NM_001375809.1		c.1510C>T	p.Leu504Phe	missense	Exon 10 of 20	NP_001362738.1
	LPIN2	NM_014646.2		c.1510C>T	p.Leu504Phe	missense	Exon 10 of 20	NP_055461.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPIN2	ENST00000677752.1	MANE Select	c.1510C>T	p.Leu504Phe	missense	Exon 10 of 20	ENSP00000504857.1
	LPIN2	ENST00000261596.9	TSL:1	c.1510C>T	p.Leu504Phe	missense	Exon 11 of 21	ENSP00000261596.4
	LPIN2	ENST00000697040.1		c.1510C>T	p.Leu504Phe	missense	Exon 10 of 20	ENSP00000513062.1

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 394 AN: 152158 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00227

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00416

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00256 AC: 643 AN: 251228 AF XY: 0.00279

Gnomad AFR exome AF: 0.000740

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00268

Gnomad NFE exome AF: 0.00363

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00326 AC: 4742 AN: 1454054 Hom.: 14 Cov.: 29 AF XY: 0.00321 AC XY: 2325 AN XY: 723910

African (AFR) AF: 0.000631 AC: 21 AN: 33306

American (AMR) AF: 0.00174 AC: 78 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000460 AC: 12 AN: 26080

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39576

South Asian (SAS) AF: 0.00230 AC: 198 AN: 86066

European-Finnish (FIN) AF: 0.00298 AC: 159 AN: 53332

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5748

European-Non Finnish (NFE) AF: 0.00371 AC: 4101 AN: 1105166

Other (OTH) AF: 0.00273 AC: 164 AN: 60070

GnomAD4 genome AF: 0.00259 AC: 395 AN: 152276 Hom.: 2 Cov.: 33 AF XY: 0.00231 AC XY: 172 AN XY: 74458

African (AFR) AF: 0.000794 AC: 33 AN: 41568

American (AMR) AF: 0.00216 AC: 33 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4830

European-Finnish (FIN) AF: 0.00227 AC: 24 AN: 10594

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00416 AC: 283 AN: 68016

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00293 Hom.: 4

Bravo AF: 0.00238

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00454 AC: 39

ExAC AF: 0.00264 AC: 321

Asia WGS AF: 0.000579 AC: 2 AN: 3470

EpiCase AF: 0.00360

EpiControl AF: 0.00308

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Majeed syndrome Uncertain:2 Benign:2 Other:1

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Sep 08, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LPIN2 c.1510C>T; p.Leu504Phe variant (rs104895500), has been reported in the literature in two individuals with suspected familial Mediterranean fever, but with alternative molecular explanations for disease (Bozgeyik 2020). The variant has also been reported in an individual with psoriasis (see link below). The variant is listed in the ClinVar database (Variation ID: 97814) and is reported in the general population with an overall allele frequency of 0.3% (724/282,640 alleles, including 3 homozygotes) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.675). Due to limited information, the clinical significance of the p.Leu504Phe variant is uncertain at this time. References: Link to variant in Infevers database: https://infevers.umai-montpellier.fr/web/search.php?n=7 Bozgeyik E et al. Next-generation screening of a panel of genes associated with periodic fever syndromes in patients with Familial Mediterranean Fever and their clinical characteristics. Genomics. 2020;112(4):2755-2762. PMID: 32199921.

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LPIN2 NM_014646.2 exon 10 p.Leu504Phe (c.1510C>T): This variant has not been reported in the literature but has been reported in 1 individual with psoriasis in the Infevers database (https://infevers.umai-montpellier.fr/web/detail_mutation.php). This variant is present in 0.3% (470/129044) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/18-2929103-G-A). This variant is present in ClinVar (Variation ID:97814). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

not provided Uncertain:1 Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 15, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 19, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LPIN2: PP2, BS2

not specified Uncertain:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Gene has limited evidence for disease association. Variant is in disease database based on personal communication. Frequency 0.33%

LPIN2-related disorder Benign:1

Sep 29, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Autoinflammatory syndrome Benign:1

Jan 31, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.96	P
Vest4		0.55
MVP		0.73
MPC		0.72
ClinPred		0.047	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.67
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs104895500; hg19: chr18-2929103;