rs10495584

Variant names:

• chr2-11819857-A-G
• rs10495584
• NM_001349206.2:c.2517+259A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001349206.2(LPIN1):​c.2517+259A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.055 in 152,276 control chromosomes in the GnomAD database, including 457 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.055 (457 hom., cov: 32)
• Consequence: LPIN1 NM_001349206.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0190
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-11819857-A-G is Benign according to our data. Variant chr2-11819857-A-G is described in ClinVar as Benign. ClinVar VariationId is 1257812.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.134 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPIN1	NM_001349206.2	MANE Select	c.2517+259A>G		intron	N/A	NP_001336135.1
	LPIN1	NM_001261428.3		c.2664+259A>G		intron	N/A	NP_001248357.1
	LPIN1	NM_001349207.2		c.2607+259A>G		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.2517+259A>G		intron	N/A	ENSP00000501331.1
	LPIN1	ENST00000256720.6	TSL:1	c.2409+259A>G		intron	N/A	ENSP00000256720.2
	LPIN1	ENST00000404113.6	TSL:1	n.2002+259A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0550 AC: 8365 AN: 152158 Hom.: 455 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0819

Gnomad ASJ AF: 0.0937

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.0266

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.0611

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0550 AC: 8378 AN: 152276 Hom.: 457 Cov.: 32 AF XY: 0.0556 AC XY: 4144 AN XY: 74468

African (AFR) AF: 0.117 AC: 4841 AN: 41540

American (AMR) AF: 0.0820 AC: 1255 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0937 AC: 325 AN: 3470

East Asian (EAS) AF: 0.143 AC: 740 AN: 5186

South Asian (SAS) AF: 0.0260 AC: 125 AN: 4816

European-Finnish (FIN) AF: 0.0102 AC: 108 AN: 10622

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0122 AC: 829 AN: 68020

Other (OTH) AF: 0.0600 AC: 127 AN: 2116

Alfa AF: 0.0355 Hom.: 442

Bravo AF: 0.0668

Asia WGS AF: 0.0640 AC: 223 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.0
DANN	Benign	0.58
PhyloP100		0.019
Mutation Taster		=100/0	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: rs10495584; hg19: chr2-11959983;