2-11815196-G-C

Position:

• chr2-11815196-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001349206.2(LPIN1):​c.2358G>C​(p.Gly786=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00919 in 1,614,106 control chromosomes in the GnomAD database, including 903 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G786G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.043 (432 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (471 hom.)
• Consequence: LPIN1 NM_001349206.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.10

Genes affected

LPIN1 (HGNC:13345): (lipin 1) This gene encodes a magnesium-ion-dependent phosphatidic acid phosphohydrolase enzyme that catalyzes the penultimate step in triglyceride synthesis including the dephosphorylation of phosphatidic acid to yield diacylglycerol. Expression of this gene is required for adipocyte differentiation and it also functions as a nuclear transcriptional coactivator with some peroxisome proliferator-activated receptors to modulate expression of other genes involved in lipid metabolism. Mutations in this gene are associated with metabolic syndrome, type 2 diabetes, acute recurrent rhabdomyolysis, and autosomal recessive acute recurrent myoglobinuria (ARARM). This gene is also a candidate for several human lipodystrophy syndromes. [provided by RefSeq, Mar 2017]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-11815196-G-C is Benign according to our data. Variant chr2-11815196-G-C is described in ClinVar as [Benign]. Clinvar id is 262591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPIN1	NM_001349206.2	c.2358G>C	p.Gly786=	synonymous_variant	18/21	ENST00000674199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPIN1	ENST00000674199.1	c.2358G>C	p.Gly786=	synonymous_variant	18/21		NM_001349206.2	P4

Frequencies

GnomAD3 genomes AF: 0.0429 AC: 6529 AN: 152146 Hom.: 427 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0194

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.0335

GnomAD3 exomes AF: 0.0123 AC: 3097 AN: 250878 Hom.: 162 AF XY: 0.00962 AC XY: 1306 AN XY: 135732

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.00914

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.000816

Gnomad SAS exome AF: 0.00294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00654

GnomAD4 exome AF: 0.00566 AC: 8275 AN: 1461842 Hom.: 471 Cov.: 32 AF XY: 0.00501 AC XY: 3640 AN XY: 727228

Gnomad4 AFR exome AF: 0.158

Gnomad4 AMR exome AF: 0.0106

Gnomad4 ASJ exome AF: 0.0128

Gnomad4 EAS exome AF: 0.000655

Gnomad4 SAS exome AF: 0.00301

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000768

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.0430 AC: 6551 AN: 152264 Hom.: 432 Cov.: 32 AF XY: 0.0412 AC XY: 3064 AN XY: 74454

Gnomad4 AFR AF: 0.145

Gnomad4 AMR AF: 0.0194

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00103

Gnomad4 OTH AF: 0.0331

Alfa AF: 0.00435 Hom.: 6

Bravo AF: 0.0496

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00202

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2017	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 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: MAF -

Myoglobinuria, acute recurrent, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.57
DANN	Benign	0.52

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: rs61732581; hg19: chr2-11955322;