2-11815196-G-C

Variant names:

• chr2-11815196-G-C
• rs61732581
• NM_001349206.2:c.2358G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001349206.2(LPIN1):​c.2358G>C​(p.Gly786Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00919 in 1,614,106 control chromosomes in the GnomAD database, including 903 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G786G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.043 (432 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (471 hom.)
• Consequence: LPIN1 NM_001349206.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.10
• Publications: 5 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-11815196-G-C is Benign according to our data. Variant chr2-11815196-G-C is described in ClinVar as Benign. ClinVar VariationId is 262591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

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.2358G>C	p.Gly786Gly	synonymous	Exon 18 of 21	NP_001336135.1	Q14693-3
	LPIN1	NM_001261428.3		c.2505G>C	p.Gly835Gly	synonymous	Exon 19 of 22	NP_001248357.1	Q14693-7
	LPIN1	NM_001349207.2		c.2448G>C	p.Gly816Gly	synonymous	Exon 18 of 21	NP_001336136.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPIN1	ENST00000674199.1	MANE Select	c.2358G>C	p.Gly786Gly	synonymous	Exon 18 of 21	ENSP00000501331.1	Q14693-3
	LPIN1	ENST00000256720.6	TSL:1	c.2250G>C	p.Gly750Gly	synonymous	Exon 17 of 20	ENSP00000256720.2	Q14693-1
	LPIN1	ENST00000404113.6	TSL:1	n.1843G>C		non_coding_transcript_exon	Exon 13 of 16

Frequencies

GnomAD3 genomes AF: 0.0429 AC: 6529 AN: 152146 Hom.: 427 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0194

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.0335

GnomAD2 exomes AF: 0.0123 AC: 3097 AN: 250878 AF XY: 0.00962

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.00914

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.000816

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00654

GnomAD4 exome AF: 0.00566 AC: 8275 AN: 1461842 Hom.: 471 Cov.: 32 AF XY: 0.00501 AC XY: 3640 AN XY: 727228

African (AFR) AF: 0.158 AC: 5303 AN: 33476

American (AMR) AF: 0.0106 AC: 474 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0128 AC: 334 AN: 26134

East Asian (EAS) AF: 0.000655 AC: 26 AN: 39700

South Asian (SAS) AF: 0.00301 AC: 260 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53402

Middle Eastern (MID) AF: 0.0375 AC: 216 AN: 5764

European-Non Finnish (NFE) AF: 0.000768 AC: 854 AN: 1111996

Other (OTH) AF: 0.0134 AC: 807 AN: 60390

GnomAD4 genome AF: 0.0430 AC: 6551 AN: 152264 Hom.: 432 Cov.: 32 AF XY: 0.0412 AC XY: 3064 AN XY: 74454

African (AFR) AF: 0.145 AC: 6029 AN: 41524

American (AMR) AF: 0.0194 AC: 297 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.00103 AC: 70 AN: 68028

Other (OTH) AF: 0.0331 AC: 70 AN: 2114

Alfa AF: 0.00435 Hom.: 6

Bravo AF: 0.0496

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00202

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Myoglobinuria, acute recurrent, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.57
DANN	Benign	0.52
PhyloP100		-1.1
Mutation Taster		=97/3	polymorphism (auto)

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: rs61732581; hg19: chr2-11955322;