11-823729-C-T

Position:

chr11-823729-C-T

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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

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=0.0033781528).

BP6

Variant 11-823729-C-T is Benign according to our data. Variant chr11-823729-C-T is described in ClinVar as [Benign]. Clinvar id is 252728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-823729-C-T is described in Lovd as [Likely_benign].

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

BS2

High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPLA2	NM_020376.4 linkuse as main transcript	c.793C>T	p.Pro265Ser	missense_variant	7/10	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.793C>T	p.Pro265Ser	missense_variant	7/10	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

GnomAD3 exomes

AF:

0.0160

AC:

3680

AN:

229710

Hom.:

AF XY:

0.0158

AC XY:

1997

AN XY:

126016

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 SAS exome

AF:

0.00470

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

Gnomad4 AFR exome

AF:

0.00377

Gnomad4 AMR exome

AF:

0.00729

Gnomad4 ASJ exome

AF:

0.0212

Gnomad4 EAS exome

AF:

0.0000548

Gnomad4 SAS exome

AF:

0.00501

Gnomad4 FIN exome

AF:

0.0289

Gnomad4 NFE exome

AF:

0.0280

Gnomad4 OTH exome

AF:

0.0209

GnomAD4 genome

AF:

0.0164

AC:

2483

AN:

150964

Hom.:

Cov.:

AF XY:

0.0157

AC XY:

1155

AN XY:

73772

show subpopulations

Gnomad4 AFR

AF:

0.00375

Gnomad4 AMR

AF:

0.0132

Gnomad4 ASJ

AF:

0.0205

Gnomad4 EAS

AF:

0.000200

Gnomad4 SAS

AF:

0.00258

Gnomad4 FIN

AF:

0.0233

Gnomad4 NFE

AF:

0.0258

Gnomad4 OTH

AF:

0.0138

Alfa

AF:

0.0182

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

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 18, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Neutral lipid storage myopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2020	This variant is associated with the following publications: (PMID: 24503134, 21170305) -

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

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

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

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

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