Genetic Variant LPIN1:p.Ser232Ser (chr2-11773719-G-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001349206.2(LPIN1):c.696G>C(p.Ser232Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,862 control chromosomes in the GnomAD database, including 120 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. S232S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0080 ( 8 hom., cov: 32)

Exomes 𝑓: 0.011 ( 112 hom. )

Consequence

LPIN1
NM_001349206.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.391

Publications

4 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, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 2-11773719-G-C is Benign according to our data. Variant chr2-11773719-G-C is described in ClinVar as Benign. ClinVar VariationId is 262596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.391 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00796 (1211/152098) while in subpopulation NFE AF = 0.0128 (873/68022). AF 95% confidence interval is 0.0121. There are 8 homozygotes in GnomAd4. There are 563 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR,AD gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LPIN1	NM_001349206.2	MANE Select	c.696G>C	p.Ser232Ser	synonymous	Exon 5 of 21	NP_001336135.1	Q14693-3
LPIN1	NM_001261428.3		c.843G>C	p.Ser281Ser	synonymous	Exon 6 of 22	NP_001248357.1	Q14693-7
LPIN1	NM_001349207.2		c.786G>C	p.Ser262Ser	synonymous	Exon 5 of 21	NP_001336136.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LPIN1	ENST00000674199.1	MANE Select	c.696G>C	p.Ser232Ser	synonymous	Exon 5 of 21	ENSP00000501331.1	Q14693-3
LPIN1	ENST00000256720.6	TSL:1	c.696G>C	p.Ser232Ser	synonymous	Exon 5 of 20	ENSP00000256720.2	Q14693-1
LPIN1	ENST00000396098.5	TSL:1	c.714G>C	p.Ser238Ser	synonymous	Exon 6 of 10	ENSP00000379405.1	Q14693-6

Frequencies

GnomAD3 genomes

AF:

0.00797

AC:

1211

AN:

151980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00203

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00864

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0128

Gnomad OTH

AF:

0.00911

GnomAD2 exomes

AF:

0.00808

AC:

2033

AN:

251476

AF XY:

0.00803

show subpopulations

Gnomad AFR exome

AF:

0.00215

Gnomad AMR exome

AF:

0.00422

Gnomad ASJ exome

AF:

0.0175

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00799

Gnomad NFE exome

AF:

0.0120

Gnomad OTH exome

AF:

0.00929

GnomAD4 exome

AF:

0.0109

AC:

15968

AN:

1461764

Hom.:

112

Cov.:

AF XY:

0.0107

AC XY:

7749

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.00182

AC:

AN:

33478

American (AMR)

AF:

0.00467

AC:

209

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0192

AC:

501

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39692

South Asian (SAS)

AF:

0.00224

AC:

193

AN:

86254

European-Finnish (FIN)

AF:

0.0102

AC:

545

AN:

53414

Middle Eastern (MID)

AF:

0.00607

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0125

AC:

13853

AN:

1111916

Other (OTH)

AF:

0.00942

AC:

569

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

757

1513

2270

3026

3783

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

514

1028

1542

2056

2570

<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:

0.00796

AC:

1211

AN:

152098

Hom.:

Cov.:

AF XY:

0.00757

AC XY:

563

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00203

AC:

AN:

41476

American (AMR)

AF:

0.00379

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0167

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00864

AC:

AN:

10538

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0128

AC:

873

AN:

68022

Other (OTH)

AF:

0.00901

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

122

182

243

304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00957

Hom.:

Bravo

AF:

0.00769

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0144

EpiControl

AF:

0.0133

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Myoglobinuria, acute recurrent, autosomal recessive (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.36

(source)

DANN

Benign

0.58

PhyloP100

-0.39

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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