dbSNP rs104895500: LPIN2:p.Leu504Phe (chr18-2929105-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001375808.2(LPIN2):c.1510C>T(p.Leu504Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0032 in 1,606,330 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0026 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0033 ( 14 hom. )

Consequence

LPIN2
NM_001375808.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:8O:1

Conservation

PhyloP100: 6.79

Publications

12 publications found

Variant links:

Genes affected

LPIN2 (HGNC:14450): (lipin 2) Mouse studies suggest that this gene functions during normal adipose tissue development and may play a role in human triglyceride metabolism. This gene represents a candidate gene for human lipodystrophy, characterized by loss of body fat, fatty liver, hypertriglyceridemia, and insulin resistance. [provided by RefSeq, Jul 2008]

LPIN2 Gene-Disease associations (from GenCC):

Majeed syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

LPIN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016277522).

BP6

Variant 18-2929105-G-A is Benign according to our data. Variant chr18-2929105-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97814.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00259 (395/152276) while in subpopulation NFE AF = 0.00416 (283/68016). AF 95% confidence interval is 0.00376. There are 2 homozygotes in GnomAd4. There are 172 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375808.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LPIN2	NM_001375808.2	MANE Select	c.1510C>T	p.Leu504Phe	missense	Exon 10 of 20	NP_001362737.1	Q92539
LPIN2	NM_001375809.1		c.1510C>T	p.Leu504Phe	missense	Exon 10 of 20	NP_001362738.1	Q92539
LPIN2	NM_014646.2		c.1510C>T	p.Leu504Phe	missense	Exon 10 of 20	NP_055461.1	Q92539

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LPIN2	ENST00000677752.1	MANE Select	c.1510C>T	p.Leu504Phe	missense	Exon 10 of 20	ENSP00000504857.1	Q92539
LPIN2	ENST00000261596.9	TSL:1	c.1510C>T	p.Leu504Phe	missense	Exon 11 of 21	ENSP00000261596.4	Q92539
LPIN2	ENST00000697040.1		c.1510C>T	p.Leu504Phe	missense	Exon 10 of 20	ENSP00000513062.1	Q92539

Frequencies

GnomAD3 genomes

AF:

0.00259

AC:

394

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.00227

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00416

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00256

AC:

643

AN:

251228

AF XY:

0.00279

show subpopulations

Gnomad AFR exome

AF:

0.000740

Gnomad AMR exome

AF:

0.00176

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00268

Gnomad NFE exome

AF:

0.00363

Gnomad OTH exome

AF:

0.00229

GnomAD4 exome

AF:

0.00326

AC:

4742

AN:

1454054

Hom.:

Cov.:

AF XY:

0.00321

AC XY:

2325

AN XY:

723910

show subpopulations

African (AFR)

AF:

0.000631

AC:

AN:

33306

American (AMR)

AF:

0.00174

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.000460

AC:

AN:

26080

East Asian (EAS)

AF:

0.0000758

AC:

AN:

39576

South Asian (SAS)

AF:

0.00230

AC:

198

AN:

86066

European-Finnish (FIN)

AF:

0.00298

AC:

159

AN:

53332

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00371

AC:

4101

AN:

1105166

Other (OTH)

AF:

0.00273

AC:

164

AN:

60070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

Heterozygous variant carriers

230

460

690

920

1150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

328

492

656

820

<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:

0.00259

AC:

395

AN:

152276

Hom.:

Cov.:

AF XY:

0.00231

AC XY:

172

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.000794

AC:

AN:

41568

American (AMR)

AF:

0.00216

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00331

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00227

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00416

AC:

283

AN:

68016

Other (OTH)

AF:

0.00190

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00293

Hom.:

Bravo

AF:

0.00238

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00454

AC:

ExAC

AF:

0.00264

AC:

321

Asia WGS

AF:

0.000579

AC:

AN:

3470

EpiCase

AF:

0.00360

EpiControl

AF:

0.00308

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Majeed syndrome (5)

Autoinflammatory syndrome (1)

LPIN2-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.078

MetaRNN

Benign

0.016

MetaSVM

Uncertain

0.16

MutationAssessor

Pathogenic

3.1

PhyloP100

6.8

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.5

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0040

Polyphen

0.96

Vest4

0.55

MVP

0.73

MPC

0.72

ClinPred

0.047

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.67

Mutation Taster

=88/12

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over