chr2-11791929-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001349206.2(LPIN1):c.1729A>G(p.Ile577Val) variant causes a missense change. The variant allele was found at a frequency of 0.00151 in 1,613,900 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 10 hom. )

Consequence

LPIN1
NM_001349206.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.99

Publications

6 publications found

Variant links:

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

LPIN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007960141).

BP6

Variant 2-11791929-A-G is Benign according to our data. Variant chr2-11791929-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00183 (278/152326) while in subpopulation AMR AF = 0.00614 (94/15312). AF 95% confidence interval is 0.00514. There are 1 homozygotes in GnomAd4. There are 140 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 10 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPIN1	NM_001349206.2 link	c.1729A>G	p.Ile577Val	missense_variant	Exon 13 of 21	ENST00000674199.1	NP_001336135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPIN1	ENST00000674199.1 link	c.1729A>G	p.Ile577Val	missense_variant	Exon 13 of 21		NM_001349206.2	ENSP00000501331.1

Frequencies

GnomAD3 genomes

AF:

0.00183

AC:

278

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00615

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00147

Gnomad OTH

AF:

0.00861

GnomAD2 exomes

AF:

0.00217

AC:

546

AN:

251358

AF XY:

0.00221

show subpopulations

Gnomad AFR exome

AF:

0.000678

Gnomad AMR exome

AF:

0.00359

Gnomad ASJ exome

AF:

0.00814

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00205

Gnomad OTH exome

AF:

0.00522

GnomAD4 exome

AF:

0.00148

AC:

2165

AN:

1461574

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

1122

AN XY:

727102

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

33468

American (AMR)

AF:

0.00400

AC:

179

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00712

AC:

186

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00217

AC:

187

AN:

86222

European-Finnish (FIN)

AF:

0.0000937

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.0168

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00116

AC:

1292

AN:

1111836

Other (OTH)

AF:

0.00301

AC:

182

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

107

215

322

430

537

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00183

AC:

278

AN:

152326

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

140

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.000553

AC:

AN:

41576

American (AMR)

AF:

0.00614

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00663

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00228

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00147

AC:

100

AN:

68022

Other (OTH)

AF:

0.00852

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00178

Hom.:

Bravo

AF:

0.00233

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00204

AC:

248

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00207

EpiControl

AF:

0.00314

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Apr 22, 2025

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria.

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LPIN1: BS2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Myoglobinuria, acute recurrent, autosomal recessive

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0

.;.;.;T;T

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.016

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

D;D;D;D;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.0080

T;T;T;T;T

MetaSVM

Benign

-0.44

MutationAssessor

Benign

0.0

.;.;.;M;.

PhyloP100

4.0

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.46

N;N;.;N;N

REVEL

Benign

0.18

Sift

Benign

0.28

T;T;.;T;T

Sift4G

Benign

0.27

T;T;T;T;T

Vest4

0.48

ClinPred

0.017

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.045

gMVP

0.27

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over