NM_020376.4:c.793C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020376.4(PNPLA2):c.793C>T(p.Pro265Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,469,646 control chromosomes in the GnomAD database, including 438 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P265P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.016 ( 32 hom., cov: 32)

Exomes 𝑓: 0.024 ( 406 hom. )

Consequence

PNPLA2
NM_020376.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.76

Publications

9 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033781528).

BP6

Variant 11-823729-C-T is Benign according to our data. Variant chr11-823729-C-T is described in ClinVar as Benign. ClinVar VariationId is 252728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0164 (2483/150964) while in subpopulation NFE AF = 0.0258 (1745/67726). AF 95% confidence interval is 0.0248. There are 32 homozygotes in GnomAd4. There are 1155 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA2	NM_020376.4 link	c.793C>T	p.Pro265Ser	missense_variant	Exon 7 of 10	ENST00000336615.9	NP_065109.1	Q96AD5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPLA2	ENST00000336615.9 link	c.793C>T	p.Pro265Ser	missense_variant	Exon 7 of 10	1	NM_020376.4	ENSP00000337701.4		Q96AD5-1

Frequencies

GnomAD3 genomes

AF:

0.0165

AC:

2484

AN:

150838

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00377

Gnomad AMI

AF:

0.0288

Gnomad AMR

AF:

0.0133

Gnomad ASJ

AF:

0.0205

Gnomad EAS

AF:

0.000200

Gnomad SAS

AF:

0.00258

Gnomad FIN

AF:

0.0233

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0258

Gnomad OTH

AF:

0.0139

GnomAD2 exomes

AF:

0.0160

AC:

3680

AN:

229710

AF XY:

0.0158

show subpopulations

Gnomad AFR exome

AF:

0.00337

Gnomad AMR exome

AF:

0.00648

Gnomad ASJ exome

AF:

0.0196

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0242

Gnomad NFE exome

AF:

0.0248

Gnomad OTH exome

AF:

0.0181

GnomAD4 exome

AF:

0.0241

AC:

31789

AN:

1318682

Hom.:

406

Cov.:

AF XY:

0.0234

AC XY:

15473

AN XY:

660326

show subpopulations

African (AFR)

AF:

0.00377

AC:

113

AN:

29944

American (AMR)

AF:

0.00729

AC:

314

AN:

43070

Ashkenazi Jewish (ASJ)

AF:

0.0212

AC:

512

AN:

24126

East Asian (EAS)

AF:

0.0000548

AC:

AN:

36512

South Asian (SAS)

AF:

0.00501

AC:

416

AN:

83048

European-Finnish (FIN)

AF:

0.0289

AC:

1323

AN:

45738

Middle Eastern (MID)

AF:

0.00501

AC:

AN:

5392

European-Non Finnish (NFE)

AF:

0.0280

AC:

27945

AN:

996516

Other (OTH)

AF:

0.0209

AC:

1137

AN:

54336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.590

Heterozygous variant carriers

1793

3586

5378

7171

8964

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

972

1944

2916

3888

4860

<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:

0.0164

AC:

2483

AN:

150964

Hom.:

Cov.:

AF XY:

0.0157

AC XY:

1155

AN XY:

73772

show subpopulations

African (AFR)

AF:

0.00375

AC:

155

AN:

41288

American (AMR)

AF:

0.0132

AC:

201

AN:

15204

Ashkenazi Jewish (ASJ)

AF:

0.0205

AC:

AN:

3460

East Asian (EAS)

AF:

0.000200

AC:

AN:

4994

South Asian (SAS)

AF:

0.00258

AC:

AN:

4648

European-Finnish (FIN)

AF:

0.0233

AC:

241

AN:

10346

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0258

AC:

1745

AN:

67726

Other (OTH)

AF:

0.0138

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.540

Heterozygous variant carriers

124

248

371

495

619

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0156

Hom.:

Bravo

AF:

0.0141

TwinsUK

AF:

0.0259

AC:

ALSPAC

AF:

0.0221

AC:

ESP6500AA

AF:

0.00391

AC:

ESP6500EA

AF:

0.0245

AC:

210

ExAC

AF:

0.0154

AC:

1843

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Sep 18, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neutral lipid storage myopathy

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Nov 10, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24503134, 21170305) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.16

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.7

PhyloP100

1.8

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.25

REVEL

Benign

0.11

Sift

Benign

0.45

Sift4G

Benign

0.71

Polyphen

0.048

Vest4

0.13

MPC

0.23

ClinPred

0.0048

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.040

gMVP

0.29

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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