chr11-821766-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_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. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

PNPLA2
NM_020376.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 0.0110

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

neutral lipid storage myopathy
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet

PNPLA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023497611).

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 37 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA2	NM_020376.4 link	c.326A>G	p.His109Arg	missense_variant	Exon 3 of 10	ENST00000336615.9	NP_065109.1	Q96AD5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PNPLA2	ENST00000336615.9 link	c.326A>G	p.His109Arg	missense_variant	Exon 3 of 10	1	NM_020376.4	ENSP00000337701.4	Q96AD5-1
PNPLA2	ENST00000525250.5 link	n.932A>G		non_coding_transcript_exon_variant	Exon 1 of 6	2
PNPLA2	ENST00000531923.1 link	n.-250A>G		upstream_gene_variant		2
PNPLA2	ENST00000534561.1 link	n.-8A>G		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000139

AC:

AN:

251320

AF XY:

0.000125

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000561

AC:

AN:

1461664

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

727128

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000358

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000574

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53218

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1111992

Other (OTH)

AF:

0.000182

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41442

American (AMR)

AF:

0.000196

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.000110

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neutral lipid storage myopathy

Uncertain:4Benign:1

Dec 02, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 08, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Oct 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 20, 2024

3billion

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant. -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.047

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.96

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.19

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.68

M_CAP

Benign

0.020

MetaRNN

Benign

0.023

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-1.3

PhyloP100

0.011

PrimateAI

Benign

0.28

PROVEAN

Benign

0.98

REVEL

Benign

0.12

Sift

Benign

1.0

Sift4G

Benign

0.65

Polyphen

0.0

Vest4

0.15

MVP

0.22

MPC

0.27

ClinPred

0.0096

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.030

gMVP

0.41

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over