dbSNP rs755967977: PNPLA2:p.Gly14Ser (chr11-819758-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_020376.4(PNPLA2):c.40G>A(p.Gly14Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000859 in 1,513,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G14G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 35)

Exomes 𝑓: 0.0000088 ( 0 hom. )

Consequence

PNPLA2
NM_020376.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.46

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

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.40G>A	p.Gly14Ser	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.40G>A	p.Gly14Ser	missense	Exon 2 of 10	ENSP00000337701.4	Q96AD5-1
PNPLA2	ENST00000869283.1		c.40G>A	p.Gly14Ser	missense	Exon 2 of 11	ENSP00000539342.1
PNPLA2	ENST00000869284.1		c.40G>A	p.Gly14Ser	missense	Exon 2 of 10	ENSP00000539343.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

123312

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:

0.00000882

AC:

AN:

1361214

Hom.:

Cov.:

AF XY:

0.00000447

AC XY:

AN XY:

671332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27686

American (AMR)

AF:

0.00

AC:

AN:

33036

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24002

East Asian (EAS)

AF:

0.00

AC:

AN:

30332

South Asian (SAS)

AF:

0.00

AC:

AN:

75768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46112

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4884

European-Non Finnish (NFE)

AF:

0.0000103

AC:

AN:

1063314

Other (OTH)

AF:

0.0000178

AC:

AN:

56080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2092

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

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:

0.000142

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000879

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neutral lipid storage myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

PhyloP100

6.5

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MutPred

0.84

Gain of sheet (P = 0.0827)

MVP

0.98

MPC

3.3

ClinPred

1.0

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.96

gMVP

0.88

Mutation Taster

=46/54

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over