11-824789-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.00

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]

(HGNC:):

ACMG classification

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	UniProt
PNPLA2	NM_020376.4	c.1442T>C	p.Leu481Pro	missense_variant	10/10	ENST00000336615.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA2	ENST00000336615.9	c.1442T>C	p.Leu481Pro	missense_variant	10/10	1	NM_020376.4	P1
PNPLA2	ENST00000529255.1	n.872T>C		non_coding_transcript_exon_variant	4/4	1
	ENST00000532946.1	n.307-926A>G		intron_variant, non_coding_transcript_variant		5
PNPLA2	ENST00000525250.5	n.2296T>C		non_coding_transcript_exon_variant	6/6	2

Frequencies

GnomAD3 genomes AF: 0.716 AC: 108843 AN: 151962 Hom.: 39320 Cov.: 35

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

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.: 58 AF XY: 0.708 AC XY: 482474 AN XY: 681768

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.: 35 AF XY: 0.711 AC XY: 52871 AN XY: 74330

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neutral lipid storage myopathy Benign:4

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	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified Benign:3

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

not provided Benign:1

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	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	12
Dann	Benign	0.97
DEOGEN2	Benign	0.080	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0000028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.67	N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.12	T
Polyphen		0.94	P
Vest4		0.075
MPC		0.36
ClinPred		0.017	T
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

Other links and lift over

dbSNP: rs1138693; hg19: chr11-824789; COSMIC: COSV60743886; COSMIC: COSV60743886;