11-824833-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_020376.4(PNPLA2):c.1486C>T(p.Arg496Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000345 in 1,534,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R496G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PNPLA2
NM_020376.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.301

Publications

1 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0069928467).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000237 (36/152178) while in subpopulation AMR AF = 0.00229 (35/15286). AF 95% confidence interval is 0.00169. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA2	NM_020376.4 link	c.1486C>T	p.Arg496Trp	missense_variant	Exon 10 of 10	ENST00000336615.9	NP_065109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPLA2	ENST00000336615.9 link	c.1486C>T	p.Arg496Trp	missense_variant	Exon 10 of 10	1	NM_020376.4	ENSP00000337701.4

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

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:

0.00

GnomAD2 exomes

AF:

0.000131

AC:

AN:

129468

AF XY:

0.000113

show subpopulations

Gnomad AFR exome

AF:

0.000165

Gnomad AMR exome

AF:

0.000618

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:

0.000251

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1382338

Hom.:

Cov.:

AF XY:

0.0000117

AC XY:

AN XY:

682208

show subpopulations

African (AFR)

AF:

0.0000634

AC:

AN:

31532

American (AMR)

AF:

0.000421

AC:

AN:

35622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25092

East Asian (EAS)

AF:

0.00

AC:

AN:

35700

South Asian (SAS)

AF:

0.00

AC:

AN:

79226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33500

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078144

Other (OTH)

AF:

0.00

AC:

AN:

57828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000237

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000404

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00229

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000196

ExAC

AF:

0.0000186

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neutral lipid storage myopathy

Uncertain:1

Feb 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 496 of the PNPLA2 protein (p.Arg496Trp). This variant is present in population databases (rs767707536, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with PNPLA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 465786). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Apr 20, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1486C>T (p.R496W) alteration is located in exon 10 (coding exon 9) of the PNPLA2 gene. This alteration results from a C to T substitution at nucleotide position 1486, causing the arginine (R) at amino acid position 496 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

PNPLA2-related disorder

Uncertain:1

Jul 18, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PNPLA2 c.1486C>T variant is predicted to result in the amino acid substitution p.Arg496Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.062% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.62

CADD

Benign

6.9

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.16

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.63

M_CAP

Benign

0.0024

MetaRNN

Benign

0.0070

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.69

PhyloP100

-0.30

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.53

REVEL

Benign

0.085

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.058

Polyphen

0.88

Vest4

0.070

MutPred

0.32

Gain of catalytic residue at R496 (P = 0.0107);

MVP

0.085

MPC

0.27

ClinPred

0.029

GERP RS

-3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.16

gMVP

0.43

Mutation Taster

=99/1

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over