Genetic Variant LPIN2:p.Arg197Gly (chr18-2951056-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001375808.2(LPIN2):c.589C>G(p.Arg197Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R197Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

LPIN2
NM_001375808.2 missense, splice_region

Scores

Splicing: ADA: 0.007166

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.40

Publications

1 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: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

LPIN2 links:

LPIN2-AS1 (HGNC:58311):

LPIN2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35891095).

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
LPIN2	NM_001375808.2	MANE Select	c.589C>G	p.Arg197Gly	missense splice_region	Exon 4 of 20	NP_001362737.1
LPIN2	NM_001375809.1		c.589C>G	p.Arg197Gly	missense splice_region	Exon 4 of 20	NP_001362738.1
LPIN2	NM_014646.2		c.589C>G	p.Arg197Gly	missense splice_region	Exon 4 of 20	NP_055461.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LPIN2	ENST00000677752.1	MANE Select	c.589C>G	p.Arg197Gly	missense splice_region	Exon 4 of 20	ENSP00000504857.1
LPIN2	ENST00000261596.9	TSL:1	c.589C>G	p.Arg197Gly	missense splice_region	Exon 5 of 21	ENSP00000261596.4
LPIN2	ENST00000697040.1		c.589C>G	p.Arg197Gly	missense splice_region	Exon 4 of 20	ENSP00000513062.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.0039

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.085

Eigen

Benign

0.079

Eigen_PC

Benign

0.053

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.84

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.36

MetaSVM

Uncertain

-0.19

MutationAssessor

Uncertain

2.6

PhyloP100

3.4

PrimateAI

Uncertain

0.48

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.37

Sift

Benign

0.20

Sift4G

Benign

0.56

Polyphen

0.97

Vest4

0.70

MutPred

0.28

Loss of solvent accessibility (P = 0.0023)

MVP

0.53

MPC

0.70

ClinPred

0.84

GERP RS

4.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.19

gMVP

0.24

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0072

dbscSNV1_RF

Benign

0.15

SpliceAI score (max)

0.10

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over