Variant 11-823586-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP3BP6_Moderate

The NM_020376.4(PNPLA2):c.756C>A(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 0.00000362 in 1,381,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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 same amino acid change has been previously reported as Likely benignin Lovd.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

PNPLA2
NM_020376.4 missense, splice_region

Scores

Splicing: ADA: 0.0001346

Clinical Significance

Likely benign criteria provided, single submitter B:1

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.772

BP6

Variant 11-823586-C-A is Benign according to our data. Variant chr11-823586-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 966646.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPLA2	NM_020376.4 linkuse as main transcript	c.756C>A	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>A	p.Asn252Lys	missense_variant, splice_region_variant	6/10	1	NM_020376.4	ENSP00000337701.4		Q96AD5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000362

AC:

AN:

1381024

Hom.:

Cov.:

AF XY:

0.00000435

AC XY:

AN XY:

689062

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000476

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neutral lipid storage myopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Benign

-0.12

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

0.83

LIST_S2

Benign

0.75

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.40

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

0.99

GERP RS

-1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00013

dbscSNV1_RF

Benign

0.18

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