2-11784824-T-C

Variant names:

• chr2-11784824-T-C
• rs3795974
• NM_001349206.2:c.1359-62T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001349206.2(LPIN1):​c.1359-62T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.605 in 1,517,020 control chromosomes in the GnomAD database, including 283,488 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31762 hom., cov: 34)
  • Exomes 𝑓: 0.60 (251726 hom.)
• Consequence: LPIN1 NM_001349206.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.12
• Publications: 31 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• hereditary recurrent myoglobinuria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-11784824-T-C is Benign according to our data. Variant chr2-11784824-T-C is described in ClinVar as Benign. ClinVar VariationId is 683089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPIN1	NM_001349206.2	c.1359-62T>C		intron_variant	Intron 9 of 20	ENST00000674199.1	NP_001336135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPIN1	ENST00000674199.1	c.1359-62T>C		intron_variant	Intron 9 of 20		NM_001349206.2	ENSP00000501331.1

Frequencies

GnomAD3 genomes AF: 0.637 AC: 96784 AN: 152054 Hom.: 31729 Cov.: 34

Gnomad AFR AF: 0.782

Gnomad AMI AF: 0.598

Gnomad AMR AF: 0.581

Gnomad ASJ AF: 0.536

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.612

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.611

Gnomad OTH AF: 0.605

GnomAD4 exome AF: 0.601 AC: 820840 AN: 1364848 Hom.: 251726 Cov.: 22 AF XY: 0.596 AC XY: 408161 AN XY: 684492

African (AFR) AF: 0.796 AC: 25109 AN: 31548

American (AMR) AF: 0.554 AC: 24718 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.536 AC: 13687 AN: 25556

East Asian (EAS) AF: 0.274 AC: 10745 AN: 39220

South Asian (SAS) AF: 0.471 AC: 39688 AN: 84280

European-Finnish (FIN) AF: 0.624 AC: 32796 AN: 52530

Middle Eastern (MID) AF: 0.616 AC: 3438 AN: 5580

European-Non Finnish (NFE) AF: 0.622 AC: 637250 AN: 1024426

Other (OTH) AF: 0.585 AC: 33409 AN: 57126

GnomAD4 genome AF: 0.637 AC: 96875 AN: 152172 Hom.: 31762 Cov.: 34 AF XY: 0.631 AC XY: 46933 AN XY: 74388

African (AFR) AF: 0.782 AC: 32492 AN: 41542

American (AMR) AF: 0.582 AC: 8894 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.536 AC: 1861 AN: 3472

East Asian (EAS) AF: 0.275 AC: 1420 AN: 5164

South Asian (SAS) AF: 0.452 AC: 2176 AN: 4818

European-Finnish (FIN) AF: 0.612 AC: 6484 AN: 10598

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.611 AC: 41555 AN: 67968

Other (OTH) AF: 0.599 AC: 1266 AN: 2112

Alfa AF: 0.615 Hom.: 115774

Bravo AF: 0.643

Asia WGS AF: 0.365 AC: 1273 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.8
DANN	Benign	0.42
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs3795974; hg19: chr2-11924950; COSMIC: COSV56763184; COSMIC: COSV56763184;