Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_020376.4(PNPLA2):c.1487_1504delGGCCCGTGATCGGGGCCC(p.Arg496_Ala501del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000515 in 1,534,660 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

PNPLA2
NM_020376.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.0430

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_020376.4.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA2	NM_020376.4	MANE Select	c.1487_1504delGGCCCGTGATCGGGGCCC	p.Arg496_Ala501del	disruptive_inframe_deletion	Exon 10 of 10	NP_065109.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PNPLA2	ENST00000336615.9	TSL:1 MANE Select	c.1487_1504delGGCCCGTGATCGGGGCCC	p.Arg496_Ala501del	disruptive_inframe_deletion	Exon 10 of 10	ENSP00000337701.4
PNPLA2	ENST00000529255.1	TSL:1	n.917_934delGGCCCGTGATCGGGGCCC		non_coding_transcript_exon	Exon 4 of 4
PNPLA2	ENST00000869283.1		c.1871_1888delGGCCCGTGATCGGGGCCC	p.Arg624_Ala629del	disruptive_inframe_deletion	Exon 11 of 11	ENSP00000539342.1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000541

AC:

AN:

129428

AF XY:

0.0000283

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000124

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.0000409

Gnomad OTH exome

AF:

0.000251

GnomAD4 exome

AF:

0.0000506

AC:

AN:

1382560

Hom.:

AF XY:

0.0000542

AC XY:

AN XY:

682358

show subpopulations

African (AFR)

AF:

0.0000317

AC:

AN:

31516

American (AMR)

AF:

0.0000842

AC:

AN:

35622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25098

East Asian (EAS)

AF:

0.00

AC:

AN:

35712

South Asian (SAS)

AF:

0.00

AC:

AN:

79232

European-Finnish (FIN)

AF:

0.0000895

AC:

AN:

33516

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.0000547

AC:

AN:

1078330

Other (OTH)

AF:

0.0000692

AC:

AN:

57840

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

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

AF:

0.0000592

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41416

American (AMR)

AF:

0.000131

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000869

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neutral lipid storage myopathy (1)

See cases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.043

Mutation Taster

=183/17

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs747915336

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over