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, G2P, Labcorp Genetics (formerly Invitae), Orphanet

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA2	NM_020376.4 link	c.1277A>G	p.Asn426Ser	missense_variant	Exon 10 of 10	ENST00000336615.9	NP_065109.1	Q96AD5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPLA2	ENST00000336615.9 link	c.1277A>G	p.Asn426Ser	missense_variant	Exon 10 of 10	1	NM_020376.4	ENSP00000337701.4		Q96AD5-1

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neutral lipid storage myopathy

Uncertain:1Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

May 31, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The N426S variant in the variant in the PNPLA2 gene has been reported previously in the heterozygous state in a healthy individual at high risk for atherosclerosis; although functional studies noted that this variant results in a protein with reduced catalytic activity, the protein localizes correctly to lipid droplets (Coassin et al., 2010). The N426S variant is observed in 98/30436 (0.32%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). The N426S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position where amino acids with similar properties to Asparagine are tolerated across species and where Serine is observed in several species. In silico analysis predicts this variant likely does not alter the protein structure/function. We interpret N426S as a variant of uncertain significance. -

PNPLA2-related disorder

Benign:1

May 24, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over