Genetic Variant PNPLA2:p.Asn252Asn (chr11-823586-C-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_020376.4(PNPLA2):c.756C>T(p.Asn252Asn) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,381,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

PNPLA2
NM_020376.4 splice_region, synonymous

Scores

Splicing: ADA: 0.001851

Clinical Significance

Not reported in ClinVar

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, Orphanet, Labcorp Genetics (formerly Invitae), G2P

PNPLA2 links:

ENSG00000255108 (HGNC:):

ENSG00000255108 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP7

Synonymous conserved (PhyloP=-0.005 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020376.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA2	NM_020376.4	MANE Select	c.756C>T	p.Asn252Asn	splice_region synonymous	Exon 6 of 10	NP_065109.1	Q96AD5-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PNPLA2	ENST00000336615.9	TSL:1 MANE Select	c.756C>T	p.Asn252Asn	splice_region synonymous	Exon 6 of 10	ENSP00000337701.4	Q96AD5-1
PNPLA2	ENST00000529255.1	TSL:1	n.44C>T		splice_region non_coding_transcript_exon	Exon 1 of 4
PNPLA2	ENST00000869283.1		c.1140C>T	p.Asn380Asn	splice_region synonymous	Exon 7 of 11	ENSP00000539342.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000829

AC:

AN:

241390

AF XY:

0.00000761

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000295

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000923

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000217

AC:

AN:

1381024

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

689062

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31652

American (AMR)

AF:

0.0000231

AC:

AN:

43370

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24594

East Asian (EAS)

AF:

0.00

AC:

AN:

36970

South Asian (SAS)

AF:

0.00

AC:

AN:

84336

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47918

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5528

European-Non Finnish (NFE)

AF:

0.00000190

AC:

AN:

1050082

Other (OTH)

AF:

0.00

AC:

AN:

56574

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

7.4

(source)

DANN

Benign

0.94

PhyloP100

-0.0050

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0019

dbscSNV1_RF

Benign

0.11

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over