11-823586-C-G

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.756C>G(p.Asn252Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,529,560 control chromosomes in the GnomAD database, including 143 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.0091 ( 10 hom., cov: 32)

Exomes 𝑓: 0.013 ( 133 hom. )

Consequence

PNPLA2
NM_020376.4 missense, splice_region

Scores

Splicing: ADA: 0.006103

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.00500

Publications

18 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=0.012045592).

BP6

Variant 11-823586-C-G is Benign according to our data. Variant chr11-823586-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261246.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 = 0.00905 (1345/148588) while in subpopulation NFE AF = 0.0141 (946/66986). AF 95% confidence interval is 0.0134. There are 10 homozygotes in GnomAd4. There are 637 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA2	NM_020376.4 link	c.756C>G	p.Asn252Lys	missense_variant, splice_region_variant	Exon 6 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.756C>G	p.Asn252Lys	missense_variant, splice_region_variant	Exon 6 of 10	1	NM_020376.4	ENSP00000337701.4		Q96AD5-1

Frequencies

GnomAD3 genomes

AF:

0.00907

AC:

1346

AN:

148426

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00289

Gnomad AMI

AF:

0.00114

Gnomad AMR

AF:

0.00413

Gnomad ASJ

AF:

0.00324

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00836

Gnomad FIN

AF:

0.0159

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0141

Gnomad OTH

AF:

0.00727

GnomAD2 exomes

AF:

0.00895

AC:

2160

AN:

241390

AF XY:

0.00913

show subpopulations

Gnomad AFR exome

AF:

0.00245

Gnomad AMR exome

AF:

0.00218

Gnomad ASJ exome

AF:

0.00307

Gnomad EAS exome

AF:

0.000222

Gnomad FIN exome

AF:

0.0126

Gnomad NFE exome

AF:

0.0138

Gnomad OTH exome

AF:

0.00933

GnomAD4 exome

AF:

0.0125

AC:

17293

AN:

1380972

Hom.:

133

Cov.:

AF XY:

0.0123

AC XY:

8459

AN XY:

689034

show subpopulations

African (AFR)

AF:

0.00196

AC:

AN:

31652

American (AMR)

AF:

0.00295

AC:

128

AN:

43370

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

24594

East Asian (EAS)

AF:

0.000108

AC:

AN:

36970

South Asian (SAS)

AF:

0.00700

AC:

590

AN:

84334

European-Finnish (FIN)

AF:

0.0152

AC:

726

AN:

47910

Middle Eastern (MID)

AF:

0.00308

AC:

AN:

5528

European-Non Finnish (NFE)

AF:

0.0144

AC:

15110

AN:

1050044

Other (OTH)

AF:

0.0101

AC:

571

AN:

56570

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1021

2043

3064

4086

5107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

556

1112

1668

2224

2780

<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:

0.00905

AC:

1345

AN:

148588

Hom.:

Cov.:

AF XY:

0.00877

AC XY:

637

AN XY:

72642

show subpopulations

African (AFR)

AF:

0.00288

AC:

118

AN:

40974

American (AMR)

AF:

0.00412

AC:

AN:

15048

Ashkenazi Jewish (ASJ)

AF:

0.00324

AC:

AN:

3400

East Asian (EAS)

AF:

0.00

AC:

AN:

4720

South Asian (SAS)

AF:

0.00833

AC:

AN:

4442

European-Finnish (FIN)

AF:

0.0159

AC:

155

AN:

9768

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0141

AC:

946

AN:

66986

Other (OTH)

AF:

0.00720

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

145

217

290

362

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00622

Hom.:

Bravo

AF:

0.00757

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.00273

AC:

ESP6500EA

AF:

0.0106

AC:

ExAC

AF:

0.00953

AC:

1150

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PNPLA2: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 19, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21170305, 30389748) -

Neutral lipid storage myopathy

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

Eigen

Benign

-0.089

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.75

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.2

PhyloP100

-0.0050

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.35

Sift

Benign

0.20

Sift4G

Benign

0.14

Polyphen

0.89

Vest4

0.84

MutPred

0.14

Gain of methylation at N252 (P = 0.0151);

MVP

0.67

MPC

0.73

ClinPred

0.039

GERP RS

-1.7

Varity_R

0.29

gMVP

0.60

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0061

dbscSNV1_RF

Benign

0.16

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over