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

Variant summary

Our verdict is Benign. Variant got -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

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:

ENSG00000255108 (HGNC:):

ENSG00000255108 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 (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 [Likely_benign]. Clinvar id is 261247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-823603-C-T is described in Lovd as [Likely_benign].

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

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	Q96AD5-1

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		Q96AD5-1

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

GnomAD3 exomes

AF:

0.000772

AC:

180

AN:

233228

Hom.:

AF XY:

0.000858

AC XY:

109

AN XY:

127056

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 SAS exome

AF:

0.00179

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

Gnomad4 AFR exome

AF:

0.000210

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00448

Gnomad4 EAS exome

AF:

0.0000334

Gnomad4 SAS exome

AF:

0.00212

Gnomad4 FIN exome

AF:

0.000123

Gnomad4 NFE exome

AF:

0.000906

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.000586

AC:

AN:

144936

Hom.:

Cov.:

AF XY:

0.000722

AC XY:

AN XY:

70680

show subpopulations

Gnomad4 AFR

AF:

0.000223

Gnomad4 AMR

AF:

0.000611

Gnomad4 ASJ

AF:

0.00479

Gnomad4 EAS

AF:

0.000231

Gnomad4 SAS

AF:

0.00147

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000579

Gnomad4 OTH

AF:

0.00145

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

DANN

Benign

0.95

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

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