18-2940605-G-T

Variant names:

• chr18-2940605-G-T
• rs139654849
• NM_001375808.2:c.698C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001375808.2(LPIN2):​c.698C>A​(p.Thr233Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000315 in 1,586,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T233I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LPIN2 NM_001375808.2 missense, splice_region
• Scores: Splicing: ADA: 0.00006527
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0660
• Publications: 2 publications found

Genes affected

LPIN2 (HGNC:14450): (lipin 2) Mouse studies suggest that this gene functions during normal adipose tissue development and may play a role in human triglyceride metabolism. This gene represents a candidate gene for human lipodystrophy, characterized by loss of body fat, fatty liver, hypertriglyceridemia, and insulin resistance. [provided by RefSeq, Jul 2008]

LPIN2 Gene-Disease associations (from GenCC):

• Majeed syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03436917).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375808.2. 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
	LPIN2	NM_001375808.2	MANE Select	c.698C>A	p.Thr233Asn	missense splice_region	Exon 5 of 20	NP_001362737.1	Q92539
	LPIN2	NM_001375809.1		c.698C>A	p.Thr233Asn	missense splice_region	Exon 5 of 20	NP_001362738.1	Q92539
	LPIN2	NM_014646.2		c.698C>A	p.Thr233Asn	missense splice_region	Exon 5 of 20	NP_055461.1	Q92539

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPIN2	ENST00000677752.1	MANE Select	c.698C>A	p.Thr233Asn	missense splice_region	Exon 5 of 20	ENSP00000504857.1	Q92539
	LPIN2	ENST00000261596.9	TSL:1	c.698C>A	p.Thr233Asn	missense splice_region	Exon 6 of 21	ENSP00000261596.4	Q92539
	LPIN2	ENST00000697040.1		c.698C>A	p.Thr233Asn	missense splice_region	Exon 5 of 20	ENSP00000513062.1	Q92539

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250162 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1434336 Hom.: 0 Cov.: 27 AF XY: 0.00000419 AC XY: 3 AN XY: 715558

African (AFR) AF: 0.00 AC: 0 AN: 32906

American (AMR) AF: 0.00 AC: 0 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25926

East Asian (EAS) AF: 0.00 AC: 0 AN: 39490

South Asian (SAS) AF: 0.00 AC: 0 AN: 85432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00000276 AC: 3 AN: 1087862

Other (OTH) AF: 0.00 AC: 0 AN: 59376

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Majeed syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	4.3
DANN	Benign	0.88
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.48	T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.8	N
PhyloP100		0.066
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.90	N
REVEL	Benign	0.22
Sift	Benign	0.26	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.082
MutPred		0.22		Loss of glycosylation at T233 (P = 0.0062)
MVP		0.20
MPC		0.27
ClinPred		0.033	T
GERP RS		-1.4
Varity_R		0.025
gMVP		0.067

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000065
dbscSNV1_RF	Benign	0.0080
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: rs139654849; hg19: chr18-2940603; COSMIC: COSV55241600; COSMIC: COSV55241600;