11-824794-G-C

Position:

• chr11-824794-G-C

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.1447G>C​(p.Gly483Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000658 in 1,532,774 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00069 (1 hom.)
• Consequence: PNPLA2 NM_020376.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: -2.16

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 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=0.0061248243).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000388 (59/152224) while in subpopulation NFE AF= 0.00075 (51/67978). AF 95% confidence interval is 0.000586. There are 0 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 34. 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	Protein	UniProt
PNPLA2	NM_020376.4	c.1447G>C	p.Gly483Arg	missense_variant	10/10	ENST00000336615.9	NP_065109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPLA2	ENST00000336615.9	c.1447G>C	p.Gly483Arg	missense_variant	10/10	1	NM_020376.4	ENSP00000337701	P1
PNPLA2	ENST00000529255.1	n.877G>C		non_coding_transcript_exon_variant	4/4	1
	ENST00000532946.1	n.307-931C>G		intron_variant, non_coding_transcript_variant		5
PNPLA2	ENST00000525250.5	n.2301G>C		non_coding_transcript_exon_variant	6/6	2

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152108 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000281 AC: 36 AN: 127950 Hom.: 0 AF XY: 0.000313 AC XY: 22 AN XY: 70280

Gnomad AFR exome AF: 0.000164

Gnomad AMR exome AF: 0.0000837

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000179

Gnomad NFE exome AF: 0.000648

Gnomad OTH exome AF: 0.000254

GnomAD4 exome AF: 0.000687 AC: 949 AN: 1380550 Hom.: 1 Cov.: 38 AF XY: 0.000662 AC XY: 451 AN XY: 681366

Gnomad4 AFR exome AF: 0.000191

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000118

Gnomad4 NFE exome AF: 0.000837

Gnomad4 OTH exome AF: 0.000572

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152224 Hom.: 0 Cov.: 34 AF XY: 0.000376 AC XY: 28 AN XY: 74438

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000363

ExAC AF: 0.000249 AC: 21

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neutral lipid storage myopathy Uncertain:2 Other:1

Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 09-29-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2022	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 483 of the PNPLA2 protein (p.Gly483Arg). This variant is present in population databases (rs557790601, gnomAD 0.07%). This missense change has been observed in individual(s) with neutral lipid storage disease with myopathy (NLSDM) (PMID: 21544567). ClinVar contains an entry for this variant (Variation ID: 465785). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect PNPLA2 function (PMID: 22990388). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.0020
DANN	Benign	0.40
DEOGEN2	Benign	0.14	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.026
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.12	T
Polyphen		0.0	B
Vest4		0.086
MutPred		0.091		Loss of catalytic residue at A482 (P = 0.1168);
MVP		0.076
MPC		0.26
ClinPred		0.014	T
GERP RS		-7.5
Varity_R		0.28
gMVP		0.28

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: rs557790601; hg19: chr11-824794; COSMIC: COSV60744903; COSMIC: COSV60744903;