rs200683247

chr11-821766-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_020376.4(PNPLA2):c.326A>G(p.His109Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000576 in 1,613,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: PNPLA2 NM_020376.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.0110

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.023497611).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000561 (82/1461664) while in subpopulation MID AF= 0.000867 (5/5768). AF 95% confidence interval is 0.000341. There are 0 homozygotes in gnomad4_exome. There are 37 alleles in male gnomad4_exome subpopulation. Median coverage is 32. 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.326A>G	p.His109Arg	missense_variant	3/10	ENST00000336615.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA2	ENST00000336615.9	c.326A>G	p.His109Arg	missense_variant	3/10	1	NM_020376.4	P1
PNPLA2	ENST00000525250.5	n.932A>G		non_coding_transcript_exon_variant	1/6	2
PNPLA2	ENST00000534561.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000139 AC: 35 AN: 251320 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135890

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000561 AC: 82 AN: 1461664 Hom.: 0 Cov.: 32 AF XY: 0.0000509 AC XY: 37 AN XY: 727128

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74358

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.00

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neutral lipid storage myopathy Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 02, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 03, 2023	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 109 of the PNPLA2 protein (p.His109Arg). This variant is present in population databases (rs200683247, 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: 306294). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PNPLA2 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 08, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	0.96
Dann	Benign	0.77
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.3	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.98	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.22
MPC		0.27
ClinPred		0.0096	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.030
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200683247; hg19: chr11-821766;