Genetic Variant PNPLA2:c.757+16C>T (chr11-823603-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020376.4(PNPLA2):c.757+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000939 in 1,134,754 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00099 ( 6 hom. )

Consequence

PNPLA2
NM_020376.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.841

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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 11-823603-C-T is Benign according to our data. Variant chr11-823603-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000586 (85/144936) while in subpopulation SAS AF = 0.00147 (6/4074). AF 95% confidence interval is 0.000641. There are 0 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA2	NM_020376.4 link	c.757+16C>T		intron_variant	Intron 6 of 9	ENST00000336615.9	NP_065109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPLA2	ENST00000336615.9 link	c.757+16C>T		intron_variant	Intron 6 of 9	1	NM_020376.4	ENSP00000337701.4

Frequencies

GnomAD3 genomes

AF:

0.000594

AC:

AN:

144784

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000223

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000612

Gnomad ASJ

AF:

0.00479

Gnomad EAS

AF:

0.000230

Gnomad SAS

AF:

0.00148

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0129

Gnomad NFE

AF:

0.000579

Gnomad OTH

AF:

0.00147

GnomAD2 exomes

AF:

0.000772

AC:

180

AN:

233228

AF XY:

0.000858

show subpopulations

Gnomad AFR exome

AF:

0.000141

Gnomad AMR exome

AF:

0.000180

Gnomad ASJ exome

AF:

0.00374

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000750

Gnomad OTH exome

AF:

0.00105

GnomAD4 exome

AF:

0.000991

AC:

981

AN:

989818

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

523

AN XY:

505056

show subpopulations

African (AFR)

AF:

0.000210

AC:

AN:

23772

American (AMR)

AF:

0.000246

AC:

AN:

40730

Ashkenazi Jewish (ASJ)

AF:

0.00448

AC:

AN:

20082

East Asian (EAS)

AF:

0.0000334

AC:

AN:

29914

South Asian (SAS)

AF:

0.00212

AC:

162

AN:

76334

European-Finnish (FIN)

AF:

0.000123

AC:

AN:

40816

Middle Eastern (MID)

AF:

0.00374

AC:

AN:

4548

European-Non Finnish (NFE)

AF:

0.000906

AC:

645

AN:

712130

Other (OTH)

AF:

0.00111

AC:

AN:

41492

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

146

195

244

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.000586

AC:

AN:

144936

Hom.:

Cov.:

AF XY:

0.000722

AC XY:

AN XY:

70680

show subpopulations

African (AFR)

AF:

0.000223

AC:

AN:

40410

American (AMR)

AF:

0.000611

AC:

AN:

14736

Ashkenazi Jewish (ASJ)

AF:

0.00479

AC:

AN:

3340

East Asian (EAS)

AF:

0.000231

AC:

AN:

4334

South Asian (SAS)

AF:

0.00147

AC:

AN:

4074

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9174

Middle Eastern (MID)

AF:

0.0104

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.000579

AC:

AN:

65658

Other (OTH)

AF:

0.00145

AC:

AN:

2064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

0.000897

Hom.:

Bravo

AF:

0.000450

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neutral lipid storage myopathy

Benign:1

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

-0.84

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.20

Position offset: -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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over