Genetic Variant PNPLA2:p.Glu368Gln (chr11-824363-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_020376.4(PNPLA2):c.1102G>C(p.Glu368Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,398,916 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 Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

PNPLA2
NM_020376.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.62

Publications

1 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:

ENSG00000255108 (HGNC:):

ENSG00000255108 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35580164).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020376.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA2	NM_020376.4	MANE Select	c.1102G>C	p.Glu368Gln	missense	Exon 9 of 10	NP_065109.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PNPLA2	ENST00000336615.9	TSL:1 MANE Select	c.1102G>C	p.Glu368Gln	missense	Exon 9 of 10	ENSP00000337701.4
PNPLA2	ENST00000529255.1	TSL:1	n.532G>C		non_coding_transcript_exon	Exon 3 of 4
PNPLA2	ENST00000869283.1		c.1486G>C	p.Glu496Gln	missense	Exon 10 of 11	ENSP00000539342.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

150350

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1398916

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690102

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31724

American (AMR)

AF:

0.00

AC:

AN:

35804

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35862

South Asian (SAS)

AF:

0.00

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47872

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5664

European-Non Finnish (NFE)

AF:

9.26e-7

AC:

AN:

1079562

Other (OTH)

AF:

0.00

AC:

AN:

58010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neutral lipid storage myopathy (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.067

MetaRNN

Benign

0.36

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.7

PhyloP100

5.6

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.64

REVEL

Benign

0.090

Sift

Benign

0.19

Sift4G

Benign

0.24

Polyphen

0.99

Vest4

0.25

MutPred

0.27

Gain of MoRF binding (P = 0.0404)

MVP

0.48

MPC

0.26

ClinPred

0.59

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.094

gMVP

0.39

Mutation Taster

=54/46

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over