dbSNP rs73375280: LPIN2:c.590+6A>G (chr18-2951049-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001375808.2(LPIN2):c.590+6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000876 in 1,613,848 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 8 hom. )

Consequence

LPIN2
NM_001375808.2 splice_region, intron

Scores

Splicing: ADA: 0.0002520

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.486

Publications

0 publications found

Variant links:

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

LPIN2 links:

LPIN2-AS1 (HGNC:58311):

LPIN2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 18-2951049-T-C is Benign according to our data. Variant chr18-2951049-T-C is described in ClinVar as Benign. ClinVar VariationId is 326648.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 = 0.00464 (706/152154) while in subpopulation AFR AF = 0.0161 (667/41494). AF 95% confidence interval is 0.0151. There are 7 homozygotes in GnomAd4. There are 309 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LPIN2	NM_001375808.2	MANE Select	c.590+6A>G	splice_region intron	N/A	NP_001362737.1	Q92539
LPIN2	NM_001375809.1		c.590+6A>G	splice_region intron	N/A	NP_001362738.1	Q92539
LPIN2	NM_014646.2		c.590+6A>G	splice_region intron	N/A	NP_055461.1	Q92539

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LPIN2	ENST00000677752.1	MANE Select	c.590+6A>G	splice_region intron	N/A	ENSP00000504857.1	Q92539
LPIN2	ENST00000261596.9	TSL:1	c.590+6A>G	splice_region intron	N/A	ENSP00000261596.4	Q92539
LPIN2	ENST00000697040.1		c.590+6A>G	splice_region intron	N/A	ENSP00000513062.1	Q92539

Frequencies

GnomAD3 genomes

AF:

0.00464

AC:

705

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0161

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00127

AC:

317

AN:

250192

AF XY:

0.000946

show subpopulations

Gnomad AFR exome

AF:

0.0175

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000484

AC:

707

AN:

1461694

Hom.:

Cov.:

AF XY:

0.000411

AC XY:

299

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.0174

AC:

582

AN:

33472

American (AMR)

AF:

0.000827

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000356

AC:

AN:

5614

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1112010

Other (OTH)

AF:

0.00121

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

115

154

192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00464

AC:

706

AN:

152154

Hom.:

Cov.:

AF XY:

0.00415

AC XY:

309

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0161

AC:

667

AN:

41494

American (AMR)

AF:

0.00190

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000208

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68006

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

103

137

171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00405

Hom.:

Bravo

AF:

0.00503

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Majeed syndrome (3)

Autoinflammatory syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

5.6

(source)

DANN

Benign

0.38

PhyloP100

-0.49

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00025

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over