rs4669781

Variant names:

• chr2-11802956-C-T
• rs4669781
• NM_001349206.2:c.1936C>T

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.1936C>T​(p.Pro646Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0482 in 1,613,376 control chromosomes in the GnomAD database, including 2,118 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (149 hom., cov: 32)
  • Exomes 𝑓: 0.049 (1969 hom.)
• Consequence: LPIN1 NM_001349206.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.19
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020134747).
• BP6: Variant 2-11802956-C-T is Benign according to our data. Variant chr2-11802956-C-T is described in ClinVar as Benign. ClinVar VariationId is 262587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0571 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.1936C>T	p.Pro646Ser	missense	Exon 15 of 21	NP_001336135.1	Q14693-3
	LPIN1	NM_001261428.3		c.2083C>T	p.Pro695Ser	missense	Exon 16 of 22	NP_001248357.1	Q14693-7
	LPIN1	NM_001349207.2		c.2026C>T	p.Pro676Ser	missense	Exon 15 of 21	NP_001336136.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPIN1	ENST00000674199.1	MANE Select	c.1936C>T	p.Pro646Ser	missense	Exon 15 of 21	ENSP00000501331.1	Q14693-3
	LPIN1	ENST00000256720.6	TSL:1	c.1828C>T	p.Pro610Ser	missense	Exon 14 of 20	ENSP00000256720.2	Q14693-1
	LPIN1	ENST00000404113.6	TSL:1	n.1421C>T		non_coding_transcript_exon	Exon 10 of 16

Frequencies

GnomAD3 genomes AF: 0.0375 AC: 5708 AN: 152230 Hom.: 150 Cov.: 32

Gnomad AFR AF: 0.00996

Gnomad AMI AF: 0.0659

Gnomad AMR AF: 0.0551

Gnomad ASJ AF: 0.0404

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0631

Gnomad FIN AF: 0.0289

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0524

Gnomad OTH AF: 0.0325

GnomAD2 exomes AF: 0.0448 AC: 11264 AN: 251296 AF XY: 0.0461

Gnomad AFR exome AF: 0.00843

Gnomad AMR exome AF: 0.0562

Gnomad ASJ exome AF: 0.0368

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0279

Gnomad NFE exome AF: 0.0532

Gnomad OTH exome AF: 0.0437

GnomAD4 exome AF: 0.0493 AC: 72046 AN: 1461028 Hom.: 1969 Cov.: 32 AF XY: 0.0497 AC XY: 36099 AN XY: 726798

African (AFR) AF: 0.00669 AC: 224 AN: 33466

American (AMR) AF: 0.0561 AC: 2511 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0372 AC: 971 AN: 26134

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0632 AC: 5447 AN: 86208

European-Finnish (FIN) AF: 0.0328 AC: 1749 AN: 53350

Middle Eastern (MID) AF: 0.0342 AC: 178 AN: 5204

European-Non Finnish (NFE) AF: 0.0524 AC: 58289 AN: 1111920

Other (OTH) AF: 0.0443 AC: 2673 AN: 60322

GnomAD4 genome AF: 0.0375 AC: 5707 AN: 152348 Hom.: 149 Cov.: 32 AF XY: 0.0368 AC XY: 2742 AN XY: 74496

African (AFR) AF: 0.00993 AC: 413 AN: 41586

American (AMR) AF: 0.0551 AC: 844 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0404 AC: 140 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0629 AC: 304 AN: 4830

European-Finnish (FIN) AF: 0.0289 AC: 307 AN: 10614

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0524 AC: 3563 AN: 68034

Other (OTH) AF: 0.0317 AC: 67 AN: 2116

Alfa AF: 0.0460 Hom.: 611

Bravo AF: 0.0360

TwinsUK AF: 0.0475 AC: 176

ALSPAC AF: 0.0558 AC: 215

ESP6500AA AF: 0.0120 AC: 53

ESP6500EA AF: 0.0535 AC: 460

ExAC AF: 0.0454 AC: 5515

Asia WGS AF: 0.0220 AC: 76 AN: 3478

EpiCase AF: 0.0484

EpiControl AF: 0.0455

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Myoglobinuria, acute recurrent, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.2
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.27
Sift	Benign	0.20	T
Sift4G	Benign	0.29	T
Polyphen		0.0020	B
Vest4		0.051
MPC		0.18
ClinPred		0.0068	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.31
Mutation Taster		=99/1	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: rs4669781; hg19: chr2-11943082; COSMIC: COSV56765296; COSMIC: COSV56765296;