chr2-11773680-G-A

Position:

• chr2-11773680-G-A

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.657G>A​(p.Leu219=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,612,766 control chromosomes in the GnomAD database, including 1,903 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (962 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (941 hom.)
• Consequence: LPIN1 NM_001349206.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.14

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=-0.91).
• BP6: Variant 2-11773680-G-A is Benign according to our data. Variant chr2-11773680-G-A is described in ClinVar as [Benign]. Clinvar id is 262595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-11773680-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LPIN1	NM_001349206.2	c.657G>A	p.Leu219=	synonymous_variant	5/21	ENST00000674199.1	NP_001336135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LPIN1	ENST00000674199.1	c.657G>A	p.Leu219=	synonymous_variant	5/21		NM_001349206.2	ENSP00000501331	P4

Frequencies

GnomAD3 genomes AF: 0.0620 AC: 9399 AN: 151682 Hom.: 960 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0231

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00791

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000809

Gnomad OTH AF: 0.0374

GnomAD3 exomes AF: 0.0174 AC: 4380 AN: 251474 Hom.: 422 AF XY: 0.0126 AC XY: 1719 AN XY: 135910

Gnomad AFR exome AF: 0.225

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.00670

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000923

Gnomad OTH exome AF: 0.00733

GnomAD4 exome AF: 0.00712 AC: 10395 AN: 1460966 Hom.: 941 Cov.: 32 AF XY: 0.00629 AC XY: 4575 AN XY: 726828

Gnomad4 AFR exome AF: 0.228

Gnomad4 AMR exome AF: 0.0122

Gnomad4 ASJ exome AF: 0.000804

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00679

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000553

Gnomad4 OTH exome AF: 0.0150

GnomAD4 genome AF: 0.0620 AC: 9419 AN: 151800 Hom.: 962 Cov.: 32 AF XY: 0.0594 AC XY: 4404 AN XY: 74160

Gnomad4 AFR AF: 0.215

Gnomad4 AMR AF: 0.0230

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00771

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000809

Gnomad4 OTH AF: 0.0375

Alfa AF: 0.0317 Hom.: 180

Bravo AF: 0.0717

Asia WGS AF: 0.0290 AC: 103 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00124

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 10, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Myoglobinuria, acute recurrent, autosomal recessive Benign:1

Benign, 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.011
DANN	Benign	0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs59909741; hg19: chr2-11913806;