chr18-2920401-G-T

Variant names:

• chr18-2920401-G-T
• rs141043192
• NM_001375808.2:c.2583C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001375808.2(LPIN2):​c.2583C>A​(p.Phe861Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F861F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LPIN2 NM_001375808.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05
• 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: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPIN2	NM_001375808.2	MANE Select	c.2583C>A	p.Phe861Leu	missense	Exon 20 of 20	NP_001362737.1	Q92539
	LPIN2	NM_001375809.1		c.2583C>A	p.Phe861Leu	missense	Exon 20 of 20	NP_001362738.1	Q92539
	LPIN2	NM_014646.2		c.2583C>A	p.Phe861Leu	missense	Exon 20 of 20	NP_055461.1	Q92539

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPIN2	ENST00000677752.1	MANE Select	c.2583C>A	p.Phe861Leu	missense	Exon 20 of 20	ENSP00000504857.1	Q92539
	LPIN2	ENST00000261596.9	TSL:1	c.2583C>A	p.Phe861Leu	missense	Exon 21 of 21	ENSP00000261596.4	Q92539
	LPIN2	ENST00000697040.1		c.2583C>A	p.Phe861Leu	missense	Exon 20 of 20	ENSP00000513062.1	Q92539

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		1.0
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.83		Gain of catalytic residue at F861 (P = 0.0794)
MVP		0.92
MPC		0.94
ClinPred		1.0	D
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.91
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs141043192; hg19: chr18-2920399;