11-824789-T-C

Position:

chr11-824789-T-C

Variant summary

Our verdict is Benign. Variant got -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. 13/19 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

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 -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. Variant chr11-824789-T-C is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
PNPLA2	NM_020376.4 linkuse as main transcript	c.1442T>C	p.Leu481Pro	missense_variant	10/10	ENST00000336615.9	NP_065109.1	Q96AD5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PNPLA2	ENST00000336615.9 linkuse as main transcript	c.1442T>C	p.Leu481Pro	missense_variant	10/10	1	NM_020376.4	ENSP00000337701.4	Q96AD5-1
PNPLA2	ENST00000529255.1 linkuse as main transcript	n.872T>C		non_coding_transcript_exon_variant	4/4	1
PNPLA2	ENST00000525250.5 linkuse as main transcript	n.2296T>C		non_coding_transcript_exon_variant	6/6	2
ENSG00000255108	ENST00000532946.1 linkuse as main transcript	n.307-926A>G		intron_variant		5

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

GnomAD3 exomes

AF:

0.672

AC:

87092

AN:

129622

Hom.:

30051

AF XY:

0.655

AC XY:

46734

AN XY:

71384

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 SAS exome

AF:

0.485

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

Gnomad4 AFR exome

AF:

0.729

Gnomad4 AMR exome

AF:

0.774

Gnomad4 ASJ exome

AF:

0.550

Gnomad4 EAS exome

AF:

0.641

Gnomad4 SAS exome

AF:

0.491

Gnomad4 FIN exome

AF:

0.737

Gnomad4 NFE exome

AF:

0.738

Gnomad4 OTH exome

AF:

0.688

GnomAD4 genome

AF:

0.716

AC:

108961

AN:

152076

Hom.:

39382

Cov.:

AF XY:

0.711

AC XY:

52871

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.727

Gnomad4 AMR

AF:

0.751

Gnomad4 ASJ

AF:

0.543

Gnomad4 EAS

AF:

0.619

Gnomad4 SAS

AF:

0.503

Gnomad4 FIN

AF:

0.721

Gnomad4 NFE

AF:

0.733

Gnomad4 OTH

AF:

0.703

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

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2018	This variant is associated with the following publications: (PMID: 21170305, 25287355) -

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

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

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

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