chr2-11677686-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001261428.3(LPIN1):c.39G>C(p.Glu13Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 1,535,318 control chromosomes in the GnomAD database, including 315,062 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 24959 hom., cov: 33)

Exomes 𝑓: 0.64 ( 290103 hom. )

Consequence

LPIN1
NM_001261428.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.349

Publications

13 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, Laboratory for Molecular Medicine, 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=2.3455743E-6).

BP6

Variant 2-11677686-G-C is Benign according to our data. Variant chr2-11677686-G-C is described in ClinVar as Benign. ClinVar VariationId is 403044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.654 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001261428.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LPIN1	NM_001261428.3	c.39G>C	p.Glu13Asp	missense	Exon 1 of 22	NP_001248357.1	Q14693-7
LPIN1	NM_001349207.2	c.39G>C	p.Glu13Asp	missense	Exon 1 of 21	NP_001336136.1
LPIN1	NM_001349208.2	c.39G>C	p.Glu13Asp	missense	Exon 1 of 21	NP_001336137.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LPIN1	ENST00000449576.6	TSL:2	c.39G>C	p.Glu13Asp	missense	Exon 1 of 22	ENSP00000397908.2	Q14693-7
LPIN1	ENST00000852426.1		c.-109G>C		5_prime_UTR	Exon 1 of 22	ENSP00000522485.1
LPIN1	ENST00000961822.1		c.-109G>C		5_prime_UTR	Exon 1 of 21	ENSP00000631881.1

Frequencies

GnomAD3 genomes

AF:

0.554

AC:

84307

AN:

152048

Hom.:

24969

Cov.:

show subpopulations

Gnomad AFR

AF:

0.345

Gnomad AMI

AF:

0.808

Gnomad AMR

AF:

0.610

Gnomad ASJ

AF:

0.607

Gnomad EAS

AF:

0.390

Gnomad SAS

AF:

0.661

Gnomad FIN

AF:

0.615

Gnomad MID

AF:

0.506

Gnomad NFE

AF:

0.659

Gnomad OTH

AF:

0.565

GnomAD2 exomes

AF:

0.606

AC:

77797

AN:

128392

AF XY:

0.613

show subpopulations

Gnomad AFR exome

AF:

0.341

Gnomad AMR exome

AF:

0.626

Gnomad ASJ exome

AF:

0.599

Gnomad EAS exome

AF:

0.390

Gnomad FIN exome

AF:

0.629

Gnomad NFE exome

AF:

0.653

Gnomad OTH exome

AF:

0.603

GnomAD4 exome

AF:

0.644

AC:

890257

AN:

1383152

Hom.:

290103

Cov.:

AF XY:

0.645

AC XY:

440311

AN XY:

682504

show subpopulations

African (AFR)

AF:

0.330

AC:

10422

AN:

31586

American (AMR)

AF:

0.615

AC:

21972

AN:

35698

Ashkenazi Jewish (ASJ)

AF:

0.597

AC:

15037

AN:

25180

East Asian (EAS)

AF:

0.411

AC:

14686

AN:

35734

South Asian (SAS)

AF:

0.659

AC:

52252

AN:

79232

European-Finnish (FIN)

AF:

0.619

AC:

20733

AN:

33470

Middle Eastern (MID)

AF:

0.512

AC:

2913

AN:

5694

European-Non Finnish (NFE)

AF:

0.664

AC:

716681

AN:

1078666

Other (OTH)

AF:

0.614

AC:

35561

AN:

57892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

16139

32278

48417

64556

80695

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18758

37516

56274

75032

93790

<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:

0.554

AC:

84321

AN:

152166

Hom.:

24959

Cov.:

AF XY:

0.554

AC XY:

41180

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.345

AC:

14325

AN:

41528

American (AMR)

AF:

0.609

AC:

9318

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.607

AC:

2107

AN:

3470

East Asian (EAS)

AF:

0.389

AC:

2005

AN:

5152

South Asian (SAS)

AF:

0.660

AC:

3185

AN:

4824

European-Finnish (FIN)

AF:

0.615

AC:

6520

AN:

10598

Middle Eastern (MID)

AF:

0.507

AC:

149

AN:

294

European-Non Finnish (NFE)

AF:

0.659

AC:

44780

AN:

67980

Other (OTH)

AF:

0.565

AC:

1195

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1828

3656

5484

7312

9140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

712

1424

2136

2848

3560

<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:

0.604

Hom.:

5242

Bravo

AF:

0.538

TwinsUK

AF:

0.649

AC:

2406

ALSPAC

AF:

0.662

AC:

2550

ExAC

AF:

0.562

AC:

8620

Asia WGS

AF:

0.546

AC:

1896

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Myoglobinuria, acute recurrent, autosomal recessive (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.35

CADD

Benign

3.5

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.33

MetaRNN

Benign

0.0000023

MetaSVM

Benign

-0.95

PhyloP100

-0.35

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.040

REVEL

Benign

0.20

Sift

Pathogenic

0.0

Vest4

0.049

MutPred

0.10

Gain of sheet (P = 0.0827)

MPC

0.16

ClinPred

0.0090

GERP RS

-0.51

PromoterAI

-0.018

Neutral

(source)

gMVP

0.069

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over