rs140634178

Positions:

chr11-824624-A-G

Variant summary

Our verdict is Benign. Variant got -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

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

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 links:

PNPLA2 (HGNC:):

PNPLA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 431910.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPLA2	NM_020376.4 linkuse as main transcript	c.1277A>G	p.Asn426Ser	missense_variant	10/10	ENST00000336615.9	NP_065109.1	Q96AD5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPLA2	ENST00000336615.9 linkuse as main transcript	c.1277A>G	p.Asn426Ser	missense_variant	10/10	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

GnomAD3 exomes

AF:

0.00117

AC:

250

AN:

213514

Hom.:

AF XY:

0.00118

AC XY:

140

AN XY:

118220

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 SAS exome

AF:

0.000877

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

Gnomad4 AFR exome

AF:

0.000541

Gnomad4 AMR exome

AF:

0.000596

Gnomad4 ASJ exome

AF:

0.0000773

Gnomad4 EAS exome

AF:

0.0000255

Gnomad4 SAS exome

AF:

0.000826

Gnomad4 FIN exome

AF:

0.000186

Gnomad4 NFE exome

AF:

0.00237

Gnomad4 OTH exome

AF:

0.00197

GnomAD4 genome

AF:

0.00122

AC:

185

AN:

151842

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

AN XY:

74232

show subpopulations

Gnomad4 AFR

AF:

0.000580

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000389

Gnomad4 SAS

AF:

0.000624

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00200

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.00196

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

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 31, 2017

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2024

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over