rs140634178

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.1277A>G(p.Asn426Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,595,158 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. N426D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 6 hom. )

Consequence

PNPLA2
NM_020376.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.486

Publications

5 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=0.005394697).

BP6

Variant 11-824624-A-G is Benign according to our data. Variant chr11-824624-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 431910.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00122 (185/151842) while in subpopulation NFE AF = 0.002 (136/67848). AF 95% confidence interval is 0.00173. There are 0 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 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.1277A>G	p.Asn426Ser	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.1277A>G	p.Asn426Ser	missense	Exon 10 of 10	ENSP00000337701.4	Q96AD5-1
PNPLA2	ENST00000529255.1	TSL:1	n.707A>G		non_coding_transcript_exon	Exon 4 of 4
PNPLA2	ENST00000869283.1		c.1661A>G	p.Asn554Ser	missense	Exon 11 of 11	ENSP00000539342.1

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

185

AN:

151736

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000581

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000388

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00200

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.00117

AC:

250

AN:

213514

AF XY:

0.00118

show subpopulations

Gnomad AFR exome

AF:

0.000684

Gnomad AMR exome

AF:

0.000610

Gnomad ASJ exome

AF:

0.000107

Gnomad EAS exome

AF:

0.0000601

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00195

Gnomad OTH exome

AF:

0.00165

GnomAD4 exome

AF:

0.00199

AC:

2869

AN:

1443316

Hom.:

Cov.:

AF XY:

0.00195

AC XY:

1400

AN XY:

717662

show subpopulations

African (AFR)

AF:

0.000541

AC:

AN:

33302

American (AMR)

AF:

0.000596

AC:

AN:

43620

Ashkenazi Jewish (ASJ)

AF:

0.0000773

AC:

AN:

25858

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39200

South Asian (SAS)

AF:

0.000826

AC:

AN:

84718

European-Finnish (FIN)

AF:

0.000186

AC:

AN:

42948

Middle Eastern (MID)

AF:

0.000353

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

0.00237

AC:

2624

AN:

1108134

Other (OTH)

AF:

0.00197

AC:

118

AN:

59864

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

177

353

530

706

883

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

106

212

318

424

530

<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:

0.00122

AC:

185

AN:

151842

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

AN XY:

74232

show subpopulations

African (AFR)

AF:

0.000580

AC:

AN:

41408

American (AMR)

AF:

0.00105

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000389

AC:

AN:

5142

South Asian (SAS)

AF:

0.000624

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00200

AC:

136

AN:

67848

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.00189

Hom.:

Bravo

AF:

0.00141

ESP6500AA

AF:

0.000915

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00115

AC:

137

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)

not provided (1)

PNPLA2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.11

(source)

DANN

Benign

0.32

DEOGEN2

Benign

0.11

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.73

M_CAP

Benign

0.0068

MetaRNN

Benign

0.0054

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.61

PhyloP100

0.49

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.11

REVEL

Benign

0.039

Sift

Benign

0.51

Sift4G

Benign

0.65

Polyphen

0.0050

Vest4

0.030

MVP

0.11

MPC

0.18

ClinPred

0.0033

GERP RS

-3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.017

gMVP

0.082

Mutation Taster

=94/6

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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