chr2-11815196-G-C

Variant names:

• chr2-11815196-G-C
• rs61732581
• NM_001349206.2:c.2358G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001349206.2(LPIN1):​c.2358G>C​(p.Gly786Gly) 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:6
• Conservation: PhyloP100: -1.10
• Publications: 5 publications found

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]

LPIN1 Gene-Disease associations (from GenCC):

• myoglobinuria, acute recurrent, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• hereditary recurrent myoglobinuria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349206.2. 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
	LPIN1	NM_001349206.2	MANE Select	c.2358G>C	p.Gly786Gly	synonymous	Exon 18 of 21	NP_001336135.1
	LPIN1	NM_001261428.3		c.2505G>C	p.Gly835Gly	synonymous	Exon 19 of 22	NP_001248357.1
	LPIN1	NM_001349207.2		c.2448G>C	p.Gly816Gly	synonymous	Exon 18 of 21	NP_001336136.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPIN1	ENST00000674199.1	MANE Select	c.2358G>C	p.Gly786Gly	synonymous	Exon 18 of 21	ENSP00000501331.1
	LPIN1	ENST00000256720.6	TSL:1	c.2250G>C	p.Gly750Gly	synonymous	Exon 17 of 20	ENSP00000256720.2
	LPIN1	ENST00000404113.6	TSL:1	n.1843G>C		non_coding_transcript_exon	Exon 13 of 16

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

GnomAD2 exomes AF: 0.0123 AC: 3097 AN: 250878 AF XY: 0.00962

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 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

African (AFR) AF: 0.158 AC: 5303 AN: 33476

American (AMR) AF: 0.0106 AC: 474 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0128 AC: 334 AN: 26134

East Asian (EAS) AF: 0.000655 AC: 26 AN: 39700

South Asian (SAS) AF: 0.00301 AC: 260 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53402

Middle Eastern (MID) AF: 0.0375 AC: 216 AN: 5764

European-Non Finnish (NFE) AF: 0.000768 AC: 854 AN: 1111996

Other (OTH) AF: 0.0134 AC: 807 AN: 60390

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

African (AFR) AF: 0.145 AC: 6029 AN: 41524

American (AMR) AF: 0.0194 AC: 297 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.00103 AC: 70 AN: 68028

Other (OTH) AF: 0.0331 AC: 70 AN: 2114

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

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: MAF

May 18, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Myoglobinuria, acute recurrent, autosomal recessive Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.57
DANN	Benign	0.52
PhyloP100		-1.1
Mutation Taster		=97/3	polymorphism (auto)

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: rs61732581; hg19: chr2-11955322;