rs10209969

Positions:

• chr2-11765750-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001349206.2(LPIN1):​c.192+17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 1,602,574 control chromosomes in the GnomAD database, including 86,792 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6129 hom., cov: 32)
  • Exomes 𝑓: 0.33 (80663 hom.)
• Consequence: LPIN1 NM_001349206.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.03

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-11765750-C-T is Benign according to our data. Variant chr2-11765750-C-T is described in ClinVar as [Benign]. Clinvar id is 96495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-11765750-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LPIN1	NM_001349206.2	c.192+17C>T		intron_variant		ENST00000674199.1	NP_001336135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LPIN1	ENST00000674199.1	c.192+17C>T		intron_variant			NM_001349206.2	ENSP00000501331	P4

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39988 AN: 151890 Hom.: 6131 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.292

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.272

GnomAD3 exomes AF: 0.295 AC: 72810 AN: 246696 Hom.: 11379 AF XY: 0.302 AC XY: 40237 AN XY: 133262

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.238

Gnomad ASJ exome AF: 0.295

Gnomad EAS exome AF: 0.202

Gnomad SAS exome AF: 0.279

Gnomad FIN exome AF: 0.360

Gnomad NFE exome AF: 0.347

Gnomad OTH exome AF: 0.317

GnomAD4 exome AF: 0.330 AC: 478202 AN: 1450564 Hom.: 80663 Cov.: 32 AF XY: 0.329 AC XY: 236794 AN XY: 720010

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.241

Gnomad4 ASJ exome AF: 0.292

Gnomad4 EAS exome AF: 0.228

Gnomad4 SAS exome AF: 0.283

Gnomad4 FIN exome AF: 0.369

Gnomad4 NFE exome AF: 0.347

Gnomad4 OTH exome AF: 0.312

GnomAD4 genome AF: 0.263 AC: 39981 AN: 152010 Hom.: 6129 Cov.: 32 AF XY: 0.263 AC XY: 19543 AN XY: 74292

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.280

Gnomad4 ASJ AF: 0.292

Gnomad4 EAS AF: 0.211

Gnomad4 SAS AF: 0.267

Gnomad4 FIN AF: 0.353

Gnomad4 NFE AF: 0.342

Gnomad4 OTH AF: 0.270

Alfa AF: 0.302 Hom.: 1349

Bravo AF: 0.247

Asia WGS AF: 0.192 AC: 667 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Myoglobinuria, acute recurrent, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.12
DANN	Benign	0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs10209969; hg19: chr2-11905876; COSMIC: COSV56770465; COSMIC: COSV56770465;