rs182948893

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_020376.4(PNPLA2):c.1327C>G(p.Leu443Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000362 in 1,597,054 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L443R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 3 hom. )

Consequence

PNPLA2
NM_020376.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 2.47

Publications

0 publications found

Variant links:

Genes affected

PNPLA2 (HGNC:30802): (patatin like phospholipase domain containing 2) This gene encodes an enzyme which catalyzes the first step in the hydrolysis of triglycerides in adipose tissue. Mutations in this gene are associated with neutral lipid storage disease with myopathy. [provided by RefSeq, Jul 2010]

PNPLA2 Gene-Disease associations (from GenCC):

neutral lipid storage myopathy
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

PNPLA2 links:

ENSG00000255108 (HGNC:):

ENSG00000255108 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010249078).

BP6

Variant 11-824674-C-G is Benign according to our data. Variant chr11-824674-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261232.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00187 (285/152272) while in subpopulation AFR AF = 0.00666 (277/41570). AF 95% confidence interval is 0.00602. There are 0 homozygotes in GnomAd4. There are 147 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020376.4. 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
	PNPLA2	NM_020376.4	MANE Select	c.1327C>G	p.Leu443Val	missense	Exon 10 of 10	NP_065109.1	Q96AD5-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PNPLA2	ENST00000336615.9	TSL:1 MANE Select	c.1327C>G	p.Leu443Val	missense	Exon 10 of 10	ENSP00000337701.4	Q96AD5-1
PNPLA2	ENST00000529255.1	TSL:1	n.757C>G		non_coding_transcript_exon	Exon 4 of 4
PNPLA2	ENST00000869283.1		c.1711C>G	p.Leu571Val	missense	Exon 11 of 11	ENSP00000539342.1

Frequencies

GnomAD3 genomes

AF:

0.00188

AC:

286

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00668

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000392

AC:

AN:

219204

AF XY:

0.000328

show subpopulations

Gnomad AFR exome

AF:

0.00555

Gnomad AMR exome

AF:

0.000269

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000582

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000203

AC:

293

AN:

1444782

Hom.:

Cov.:

AF XY:

0.000156

AC XY:

112

AN XY:

719024

show subpopulations

African (AFR)

AF:

0.00759

AC:

253

AN:

33346

American (AMR)

AF:

0.000249

AC:

AN:

44260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25958

East Asian (EAS)

AF:

0.00

AC:

AN:

39446

South Asian (SAS)

AF:

0.0000234

AC:

AN:

85606

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40572

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1109904

Other (OTH)

AF:

0.000400

AC:

AN:

60004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00187

AC:

285

AN:

152272

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

147

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00666

AC:

277

AN:

41570

American (AMR)

AF:

0.000392

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67986

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000539

Hom.:

Bravo

AF:

0.00209

ESP6500AA

AF:

0.00254

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000495

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3470

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neutral lipid storage myopathy (2)

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.8

PhyloP100

2.5

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.62

REVEL

Benign

0.12

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.36

MVP

0.53

MPC

0.75

ClinPred

0.065

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.50

Mutation Taster

=37/63

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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