rs139576982

chr11-821676-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BS1_Supporting

The NM_020376.4(PNPLA2):c.236G>A(p.Arg79Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000641 in 1,613,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R79W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00066 (0 hom.)
• Consequence: PNPLA2 NM_020376.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 7.86

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28251272).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000466 (71/152326) while in subpopulation SAS AF= 0.00104 (5/4828). AF 95% confidence interval is 0.000612. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA2	NM_020376.4	c.236G>A	p.Arg79Gln	missense_variant	3/10	ENST00000336615.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA2	ENST00000336615.9	c.236G>A	p.Arg79Gln	missense_variant	3/10	1	NM_020376.4	P1
PNPLA2	ENST00000525250.5	n.842G>A		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes AF: 0.000466 AC: 71 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000674 AC: 169 AN: 250926 Hom.: 0 AF XY: 0.000715 AC XY: 97 AN XY: 135740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000660 AC: 964 AN: 1461560 Hom.: 0 Cov.: 32 AF XY: 0.000673 AC XY: 489 AN XY: 727064

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000614

Gnomad4 FIN exome AF: 0.00168

Gnomad4 NFE exome AF: 0.000701

Gnomad4 OTH exome AF: 0.000546

GnomAD4 genome AF: 0.000466 AC: 71 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.000416 AC XY: 31 AN XY: 74488

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00351 Hom.: 0

Bravo AF: 0.000374

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000667 AC: 81

EpiCase AF: 0.000545

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neutral lipid storage myopathy Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 13, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 25, 2020	A heterozygous missense variant was identified, NM_020376.3(PNPLA2):c.236G>A in exon 3 of 10 of the PNPLA2 gene. This substitution is predicted to create a minor amino acid change from arginine to glutamine at position 79 of the protein, NP_065109.1(PNPLA2):p.(Arg79Gln). The arginine at this position has high conservation (100 vertebrates, UCSC), and is located within the Patatin-like phospholipase domain. In silico software predicts this variant to be damaging (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.07% (189 heterozygotes, 0 homozygotes). In addition, functional studies show that this variant causes impaired catalytic activity (Coassin, S. et al . (2010)). This variant has not been previously reported in clinical cases. Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with POTENTIAL CLINICAL RELEVANCE. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 31, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 79 of the PNPLA2 protein (p.Arg79Gln). This variant is present in population databases (rs139576982, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of PNPLA2-related conditions (PMID: 32041611). ClinVar contains an entry for this variant (Variation ID: 465789). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects PNPLA2 function (PMID: 21170305). 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. -
Likely benign, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.25
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.54
Sift	Benign	0.092	T
Sift4G	Uncertain	0.056	T
Polyphen		1.0	D
Vest4		0.79
MVP		0.92
MPC		0.85
ClinPred		0.11	T
GERP RS		4.5
Varity_R		0.43
gMVP		0.59

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: rs139576982; hg19: chr11-821676; COSMIC: COSV60744455; COSMIC: COSV60744455;