2-11771635-C-G

Variant names:

• chr2-11771635-C-G
• rs11538448
• NM_001349206.2:c.552C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001349206.2(LPIN1):​c.552C>G​(p.Ile184Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,451,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I184I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: LPIN1 NM_001349206.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.748
• Publications: 14 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07737288).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPIN1	NM_001349206.2	MANE Select	c.552C>G	p.Ile184Met	missense	Exon 4 of 21	NP_001336135.1	Q14693-3
	LPIN1	NM_001261428.3		c.699C>G	p.Ile233Met	missense	Exon 5 of 22	NP_001248357.1	Q14693-7
	LPIN1	NM_001349207.2		c.642C>G	p.Ile214Met	missense	Exon 4 of 21	NP_001336136.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPIN1	ENST00000674199.1	MANE Select	c.552C>G	p.Ile184Met	missense	Exon 4 of 21	ENSP00000501331.1	Q14693-3
	LPIN1	ENST00000256720.6	TSL:1	c.552C>G	p.Ile184Met	missense	Exon 4 of 20	ENSP00000256720.2	Q14693-1
	LPIN1	ENST00000396098.5	TSL:1	c.570C>G	p.Ile190Met	missense	Exon 5 of 10	ENSP00000379405.1	Q14693-6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1451628 Hom.: 0 Cov.: 33 AF XY: 0.00000416 AC XY: 3 AN XY: 720908

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 42632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25896

East Asian (EAS) AF: 0.00 AC: 0 AN: 39448

South Asian (SAS) AF: 0.00 AC: 0 AN: 84422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000452 AC: 5 AN: 1107120

Other (OTH) AF: 0.0000166 AC: 1 AN: 60144

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 539

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.0023	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	0.19
DANN	Benign	0.94
DEOGEN2	Benign	0.088	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.75
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.74	N
REVEL	Uncertain	0.38
Sift	Benign	0.28	T
Sift4G	Benign	0.28	T
Polyphen		0.075	B
Vest4		0.26
MutPred		0.20		Gain of catalytic residue at I184 (P = 0.1089)
MVP		0.52
MPC		0.19
ClinPred		0.33	T
GERP RS		-9.1
Varity_R		0.066
gMVP		0.20
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

dbSNP: rs11538448; hg19: chr2-11911761;