chr2-11771635-C-T

Position:

• chr2-11771635-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001349206.2(LPIN1):​c.552C>T​(p.Ile184=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,603,708 control chromosomes in the GnomAD database, including 14,091 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (897 hom., cov: 33)
  • Exomes 𝑓: 0.13 (13194 hom.)
• Consequence: LPIN1 NM_001349206.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.748

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 2-11771635-C-T is Benign according to our data. Variant chr2-11771635-C-T is described in ClinVar as [Benign]. Clinvar id is 96497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-11771635-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.748 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LPIN1	NM_001349206.2	c.552C>T	p.Ile184=	synonymous_variant	4/21	ENST00000674199.1	NP_001336135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LPIN1	ENST00000674199.1	c.552C>T	p.Ile184=	synonymous_variant	4/21		NM_001349206.2	ENSP00000501331	P4

Frequencies

GnomAD3 genomes AF: 0.0939 AC: 14285 AN: 152148 Hom.: 900 Cov.: 33

Gnomad AFR AF: 0.0252

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.0825

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0626

Gnomad FIN AF: 0.0926

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.110

GnomAD3 exomes AF: 0.0980 AC: 22673 AN: 231410 Hom.: 1401 AF XY: 0.101 AC XY: 12545 AN XY: 124308

Gnomad AFR exome AF: 0.0225

Gnomad AMR exome AF: 0.0551

Gnomad ASJ exome AF: 0.126

Gnomad EAS exome AF: 0.000412

Gnomad SAS exome AF: 0.0685

Gnomad FIN exome AF: 0.0992

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.128 AC: 185175 AN: 1451442 Hom.: 13194 Cov.: 33 AF XY: 0.127 AC XY: 91739 AN XY: 720786

Gnomad4 AFR exome AF: 0.0198

Gnomad4 AMR exome AF: 0.0591

Gnomad4 ASJ exome AF: 0.122

Gnomad4 EAS exome AF: 0.000304

Gnomad4 SAS exome AF: 0.0729

Gnomad4 FIN exome AF: 0.0951

Gnomad4 NFE exome AF: 0.144

Gnomad4 OTH exome AF: 0.115

GnomAD4 genome AF: 0.0937 AC: 14272 AN: 152266 Hom.: 897 Cov.: 33 AF XY: 0.0914 AC XY: 6802 AN XY: 74448

Gnomad4 AFR AF: 0.0251

Gnomad4 AMR AF: 0.0823

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0622

Gnomad4 FIN AF: 0.0926

Gnomad4 NFE AF: 0.145

Gnomad4 OTH AF: 0.108

Alfa AF: 0.114 Hom.: 538

Bravo AF: 0.0894

Asia WGS AF: 0.0310 AC: 110 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 07, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -

not provided Benign:2

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

Myoglobinuria, acute recurrent, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.46
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs11538448; hg19: chr2-11911761;