11-824789-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020376.4(PNPLA2):c.1442T>C(p.Leu481Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.716 in 1,533,332 control chromosomes in the GnomAD database, including 396,632 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.72 ( 39382 hom., cov: 35)

Exomes 𝑓: 0.72 ( 357250 hom. )

Consequence

PNPLA2
NM_020376.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.00

Publications

48 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.8413976E-6).

BP6

Variant 11-824789-T-C is Benign according to our data. Variant chr11-824789-T-C is described in ClinVar as [Benign]. Clinvar id is 261236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA2	NM_020376.4 link	c.1442T>C	p.Leu481Pro	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.1442T>C	p.Leu481Pro	missense_variant	Exon 10 of 10	1	NM_020376.4	ENSP00000337701.4		Q96AD5-1

Frequencies

GnomAD3 genomes

AF:

0.716

AC:

108843

AN:

151962

Hom.:

39320

Cov.:

show subpopulations

Gnomad AFR

AF:

0.727

Gnomad AMI

AF:

0.772

Gnomad AMR

AF:

0.751

Gnomad ASJ

AF:

0.543

Gnomad EAS

AF:

0.619

Gnomad SAS

AF:

0.502

Gnomad FIN

AF:

0.721

Gnomad MID

AF:

0.576

Gnomad NFE

AF:

0.733

Gnomad OTH

AF:

0.699

GnomAD2 exomes

AF:

0.672

AC:

87092

AN:

129622

AF XY:

0.655

show subpopulations

Gnomad AFR exome

AF:

0.729

Gnomad AMR exome

AF:

0.778

Gnomad ASJ exome

AF:

0.549

Gnomad EAS exome

AF:

0.603

Gnomad FIN exome

AF:

0.735

Gnomad NFE exome

AF:

0.726

Gnomad OTH exome

AF:

0.670

GnomAD4 exome

AF:

0.716

AC:

988563

AN:

1381256

Hom.:

357250

Cov.:

AF XY:

0.708

AC XY:

482474

AN XY:

681768

show subpopulations

African (AFR)

AF:

0.729

AC:

22896

AN:

31418

American (AMR)

AF:

0.774

AC:

27224

AN:

35176

Ashkenazi Jewish (ASJ)

AF:

0.550

AC:

13684

AN:

24894

East Asian (EAS)

AF:

0.641

AC:

22900

AN:

35716

South Asian (SAS)

AF:

0.491

AC:

38915

AN:

79240

European-Finnish (FIN)

AF:

0.737

AC:

24979

AN:

33910

Middle Eastern (MID)

AF:

0.559

AC:

3174

AN:

5676

European-Non Finnish (NFE)

AF:

0.738

AC:

795103

AN:

1077530

Other (OTH)

AF:

0.688

AC:

39688

AN:

57696

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

16758

33517

50275

67034

83792

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.716

AC:

108961

AN:

152076

Hom.:

39382

Cov.:

AF XY:

0.711

AC XY:

52871

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.727

AC:

30197

AN:

41514

American (AMR)

AF:

0.751

AC:

11485

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.543

AC:

1884

AN:

3472

East Asian (EAS)

AF:

0.619

AC:

3188

AN:

5148

South Asian (SAS)

AF:

0.503

AC:

2421

AN:

4816

European-Finnish (FIN)

AF:

0.721

AC:

7641

AN:

10602

Middle Eastern (MID)

AF:

0.575

AC:

168

AN:

292

European-Non Finnish (NFE)

AF:

0.733

AC:

49786

AN:

67912

Other (OTH)

AF:

0.703

AC:

1487

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1642

3284

4925

6567

8209

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.653

Hom.:

3950

Bravo

AF:

0.719

TwinsUK

AF:

0.749

AC:

2778

ALSPAC

AF:

0.740

AC:

2853

ESP6500AA

AF:

0.704

AC:

1997

ESP6500EA

AF:

0.708

AC:

4530

ExAC

AF:

0.579

AC:

46359

Asia WGS

AF:

0.599

AC:

2082

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neutral lipid storage myopathy

Benign:4

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Jul 13, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21170305, 25287355) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.080

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.17

MetaRNN

Benign

0.0000028

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.0

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.67

REVEL

Benign

0.13

Sift

Pathogenic

0.0

Sift4G

Benign

0.12

Polyphen

0.94

Vest4

0.075

MPC

0.36

ClinPred

0.017

Varity_R

0.12

gMVP

0.17

Mutation Taster

=100/0

polymorphism (auto)

(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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11-824789-T-C

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