rs768189312

Variant names:

• chr18-2931430-C-T
• rs768189312
• NM_001375808.2:c.1282G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014646.2(LPIN2):​c.1282G>A​(p.Gly428Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,591,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: LPIN2 NM_014646.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.09
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07635465).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014646.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPIN2	NM_001375808.2	MANE Select	c.1282G>A	p.Gly428Ser	missense	Exon 9 of 20	NP_001362737.1
	LPIN2	NM_001375809.1		c.1282G>A	p.Gly428Ser	missense	Exon 9 of 20	NP_001362738.1
	LPIN2	NM_014646.2		c.1282G>A	p.Gly428Ser	missense	Exon 9 of 20	NP_055461.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPIN2	ENST00000677752.1	MANE Select	c.1282G>A	p.Gly428Ser	missense	Exon 9 of 20	ENSP00000504857.1
	LPIN2	ENST00000261596.9	TSL:1	c.1282G>A	p.Gly428Ser	missense	Exon 10 of 21	ENSP00000261596.4
	LPIN2	ENST00000697040.1		c.1282G>A	p.Gly428Ser	missense	Exon 9 of 20	ENSP00000513062.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000673 AC: 14 AN: 207918 AF XY: 0.0000628

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000979

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000548

Gnomad NFE exome AF: 0.0000221

Gnomad OTH exome AF: 0.000187

GnomAD4 exome AF: 0.0000417 AC: 60 AN: 1438954 Hom.: 0 Cov.: 31 AF XY: 0.0000434 AC XY: 31 AN XY: 713774

African (AFR) AF: 0.00 AC: 0 AN: 33122

American (AMR) AF: 0.00 AC: 0 AN: 40408

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 37 AN: 25590

East Asian (EAS) AF: 0.00 AC: 0 AN: 38900

South Asian (SAS) AF: 0.0000359 AC: 3 AN: 83642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 0.00000909 AC: 10 AN: 1100512

Other (OTH) AF: 0.000168 AC: 10 AN: 59654

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000151 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000579 AC: 7

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Autoinflammatory syndrome (1)
-	1	-	Majeed syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.90
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.1
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.29
Sift	Benign	0.13	T
Sift4G	Benign	0.44	T
Polyphen		0.79	P
Vest4		0.22
MutPred		0.13		Gain of phosphorylation at G428 (P = 0.0059)
MVP		0.33
MPC		0.24
ClinPred		0.058	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.043
gMVP		0.19
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs768189312; hg19: chr18-2931428;