18-2920327-G-A

Position:

chr18-2920327-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP3_ModerateBS1_Supporting

The NM_001375808.2(LPIN2):c.2657C>T(p.Pro886Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000762 in 1,614,146 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000071 ( 1 hom. )

Consequence

LPIN2
NM_001375808.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.61

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]

LPIN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.915

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000711 (104/1461808) while in subpopulation EAS AF= 0.000882 (35/39700). AF 95% confidence interval is 0.000651. There are 1 homozygotes in gnomad4_exome. There are 53 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LPIN2	NM_001375808.2 linkuse as main transcript	c.2657C>T	p.Pro886Leu	missense_variant	20/20	ENST00000677752.1	NP_001362737.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LPIN2	ENST00000677752.1 linkuse as main transcript	c.2657C>T	p.Pro886Leu	missense_variant	20/20		NM_001375808.2	ENSP00000504857.1		Q92539

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251292

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000711

AC:

104

AN:

1461808

Hom.:

Cov.:

AF XY:

0.0000729

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000882

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000468

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000125

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000216

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000136

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Majeed syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 06, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 886 of the LPIN2 protein (p.Pro886Leu). This variant is present in population databases (rs147203309, gnomAD 0.03%). 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: 326633). 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"). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2024

The c.2657C>T (p.P886L) alteration is located in exon 20 (coding exon 19) of the LPIN2 gene. This alteration results from a C to T substitution at nucleotide position 2657, causing the proline (P) at amino acid position 886 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autoinflammatory syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 24, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.44

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

3.3

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-7.1

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.84

MVP

0.66

MPC

0.84

ClinPred

0.72

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.67

gMVP

0.83

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over