11-823586-C-G

Position:

chr11-823586-C-G

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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

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 links:

PNPLA2 (HGNC:):

PNPLA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 261246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-823586-C-G is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPLA2	NM_020376.4 linkuse as main transcript	c.756C>G	p.Asn252Lys	missense_variant, splice_region_variant	6/10	ENST00000336615.9	NP_065109.1	Q96AD5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPLA2	ENST00000336615.9 linkuse as main transcript	c.756C>G	p.Asn252Lys	missense_variant, splice_region_variant	6/10	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

GnomAD3 exomes

AF:

0.00895

AC:

2160

AN:

241390

Hom.:

AF XY:

0.00913

AC XY:

1200

AN XY:

131376

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 SAS exome

AF:

0.00690

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

Gnomad4 AFR exome

AF:

0.00196

Gnomad4 AMR exome

AF:

0.00295

Gnomad4 ASJ exome

AF:

0.00346

Gnomad4 EAS exome

AF:

0.000108

Gnomad4 SAS exome

AF:

0.00700

Gnomad4 FIN exome

AF:

0.0152

Gnomad4 NFE exome

AF:

0.0144

Gnomad4 OTH exome

AF:

0.0101

GnomAD4 genome

AF:

0.00905

AC:

1345

AN:

148588

Hom.:

Cov.:

AF XY:

0.00877

AC XY:

637

AN XY:

72642

show subpopulations

Gnomad4 AFR

AF:

0.00288

Gnomad4 AMR

AF:

0.00412

Gnomad4 ASJ

AF:

0.00324

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00833

Gnomad4 FIN

AF:

0.0159

Gnomad4 NFE

AF:

0.0141

Gnomad4 OTH

AF:

0.00720

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2021	This variant is associated with the following publications: (PMID: 21170305, 30389748) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	PNPLA2: BS1, BS2 -

Neutral lipid storage myopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over