rs142083008

Variant names:

• chr2-11788351-C-T
• rs142083008
• NM_001349206.2:c.1644-36C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001261428.3(LPIN1):​c.1791-36C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,528,396 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: LPIN1 NM_001261428.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.75
• Publications: 0 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 2-11788351-C-T is Benign according to our data. Variant chr2-11788351-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 262584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0041 (624/152242) while in subpopulation AFR AF = 0.0103 (426/41532). AF 95% confidence interval is 0.00945. There are 2 homozygotes in GnomAd4. There are 282 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001261428.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPIN1	NM_001349206.2	MANE Select	c.1644-36C>T		intron	N/A	NP_001336135.1
	LPIN1	NM_001261428.3		c.1791-36C>T		intron	N/A	NP_001248357.1
	LPIN1	NM_001349207.2		c.1734-36C>T		intron	N/A	NP_001336136.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPIN1	ENST00000674199.1	MANE Select	c.1644-36C>T		intron	N/A	ENSP00000501331.1
	LPIN1	ENST00000256720.6	TSL:1	c.1536-36C>T		intron	N/A	ENSP00000256720.2
	LPIN1	ENST00000404113.6	TSL:1	n.1129-36C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 617 AN: 152124 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00200 AC: 502 AN: 251272 AF XY: 0.00190

Gnomad AFR exome AF: 0.0108

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.0100

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00122 AC: 1673 AN: 1376154 Hom.: 3 Cov.: 21 AF XY: 0.00121 AC XY: 838 AN XY: 689938

African (AFR) AF: 0.00981 AC: 311 AN: 31718

American (AMR) AF: 0.00193 AC: 86 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.00934 AC: 239 AN: 25590

East Asian (EAS) AF: 0.00 AC: 0 AN: 39286

South Asian (SAS) AF: 0.000296 AC: 25 AN: 84560

European-Finnish (FIN) AF: 0.0000938 AC: 5 AN: 53316

Middle Eastern (MID) AF: 0.00287 AC: 16 AN: 5578

European-Non Finnish (NFE) AF: 0.000823 AC: 851 AN: 1034092

Other (OTH) AF: 0.00244 AC: 140 AN: 57420

GnomAD4 genome AF: 0.00410 AC: 624 AN: 152242 Hom.: 2 Cov.: 32 AF XY: 0.00379 AC XY: 282 AN XY: 74426

African (AFR) AF: 0.0103 AC: 426 AN: 41532

American (AMR) AF: 0.00399 AC: 61 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00129 AC: 88 AN: 68032

Other (OTH) AF: 0.00474 AC: 10 AN: 2108

Alfa AF: 0.00270 Hom.: 0

Bravo AF: 0.00497

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.055
DANN	Benign	0.78
PhyloP100		-1.8
Mutation Taster		=100/0	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: rs142083008; hg19: chr2-11928477;