rs61735393

Positions:

• chr18-2925361-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001375808.2(LPIN2):​c.1801G>A​(p.Glu601Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00912 in 1,614,068 control chromosomes in the GnomAD database, including 113 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0092 (100 hom.)
• Consequence: LPIN2 NM_001375808.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.38

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004709542).
• BP6: Variant 18-2925361-C-T is Benign according to our data. Variant chr18-2925361-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 138133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-2925361-C-T is described in Lovd as [Benign]. Variant chr18-2925361-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00833 (1268/152230) while in subpopulation AMR AF= 0.0186 (285/15296). AF 95% confidence interval is 0.0169. There are 13 homozygotes in gnomad4. There are 617 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPIN2	NM_001375808.2	c.1801G>A	p.Glu601Lys	missense_variant	14/20	ENST00000677752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPIN2	ENST00000677752.1	c.1801G>A	p.Glu601Lys	missense_variant	14/20		NM_001375808.2	P1

Frequencies

GnomAD3 genomes AF: 0.00834 AC: 1269 AN: 152112 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00892 AC: 2243 AN: 251458 Hom.: 11 AF XY: 0.00912 AC XY: 1240 AN XY: 135902

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.0121

Gnomad ASJ exome AF: 0.0383

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00304

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.0145

GnomAD4 exome AF: 0.00920 AC: 13451 AN: 1461838 Hom.: 100 Cov.: 32 AF XY: 0.00916 AC XY: 6663 AN XY: 727224

Gnomad4 AFR exome AF: 0.00230

Gnomad4 AMR exome AF: 0.0126

Gnomad4 ASJ exome AF: 0.0388

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00328

Gnomad4 FIN exome AF: 0.00137

Gnomad4 NFE exome AF: 0.00942

Gnomad4 OTH exome AF: 0.0124

GnomAD4 genome AF: 0.00833 AC: 1268 AN: 152230 Hom.: 13 Cov.: 32 AF XY: 0.00829 AC XY: 617 AN XY: 74432

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.0340

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.000943

Gnomad4 NFE AF: 0.0103

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0116 Hom.: 20

Bravo AF: 0.00952

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0124 AC: 107

ExAC AF: 0.00790 AC: 959

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0140

EpiControl AF: 0.0129

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Majeed syndrome Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 18, 2019	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 30, 2023	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2018	This variant is associated with the following publications: (PMID: 27884173, 22995991, 26764160) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	LPIN2: BS1, BS2 -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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: HGMD entry based on exitence in disease database and personal communication (http://fmf.igh.cnrs.fr/ISSAID/infevers/detail_mutation.php), reportedly identified in patient(s) with psioriasis, but no inofmration is available. MAF 1.2%. -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 31, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.095	T
Eigen	Benign	-0.071
Eigen_PC	Benign	-0.0066
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.96	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.87	N
REVEL	Uncertain	0.34
Sift	Benign	0.13	T
Sift4G	Benign	0.35	T
Polyphen		0.31	B
Vest4		0.55
MVP		0.57
MPC		0.27
ClinPred		0.0096	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.092
gMVP		0.34

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

LitVar

Other links and lift over

dbSNP: rs61735393; hg19: chr18-2925359;