Genetic Variant PNPLA2:p.Arg4Pro (chr11-819729-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020376.4(PNPLA2):c.11G>C(p.Arg4Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000523 in 1,339,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 35)

Exomes 𝑓: 0.0000052 ( 0 hom. )

Consequence

PNPLA2
NM_020376.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.397

Publications

0 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: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

PNPLA2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.021873087).

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.11G>C	p.Arg4Pro	missense	Exon 2 of 10	NP_065109.1	Q96AD5-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PNPLA2	ENST00000336615.9	TSL:1 MANE Select	c.11G>C	p.Arg4Pro	missense	Exon 2 of 10	ENSP00000337701.4	Q96AD5-1
PNPLA2	ENST00000869283.1		c.11G>C	p.Arg4Pro	missense	Exon 2 of 11	ENSP00000539342.1
PNPLA2	ENST00000869284.1		c.11G>C	p.Arg4Pro	missense	Exon 2 of 10	ENSP00000539343.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000523

AC:

AN:

1339644

Hom.:

Cov.:

AF XY:

0.00000455

AC XY:

AN XY:

659298

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27042

American (AMR)

AF:

0.00

AC:

AN:

29394

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23632

East Asian (EAS)

AF:

0.00

AC:

AN:

28938

South Asian (SAS)

AF:

0.00

AC:

AN:

74160

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4376

European-Non Finnish (NFE)

AF:

0.00000665

AC:

AN:

1052616

Other (OTH)

AF:

0.00

AC:

AN:

55102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.077

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.69

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.022

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.14

PhyloP100

-0.40

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.96

REVEL

Benign

0.020

Sift

Benign

0.28

Sift4G

Benign

0.26

Polyphen

0.0010

Vest4

0.055

MutPred

0.27

Gain of glycosylation at R4 (P = 0.0183)

MVP

0.11

MPC

2.4

ClinPred

0.096

GERP RS

-2.3

Varity_R

0.19

gMVP

0.40

Mutation Taster

=79/21

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over