11-823809-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020376.4(PNPLA2):c.873C>G(p.Pro291=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,601,182 control chromosomes in the GnomAD database, including 52,688 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P291P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.21 (4059 hom., cov: 32)
  • Exomes 𝑓: 0.25 (48629 hom.)
• Consequence: PNPLA2 NM_020376.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.58

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-823809-C-G is Benign according to our data. Variant chr11-823809-C-G is described in ClinVar as [Benign]. Clinvar id is 261248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-823809-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA2	NM_020376.4	c.873C>G	p.Pro291=	synonymous_variant	7/10	ENST00000336615.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA2	ENST00000336615.9	c.873C>G	p.Pro291=	synonymous_variant	7/10	1	NM_020376.4	P1
	ENST00000532946.1	n.361G>C		non_coding_transcript_exon_variant	3/3	5

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32497 AN: 151900 Hom.: 4060 Cov.: 32

Gnomad AFR AF: 0.0979

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.398

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.413

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.246

GnomAD3 exomes AF: 0.273 AC: 60745 AN: 222352 Hom.: 9217 AF XY: 0.289 AC XY: 35073 AN XY: 121488

Gnomad AFR exome AF: 0.0939

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.391

Gnomad EAS exome AF: 0.401

Gnomad SAS exome AF: 0.425

Gnomad FIN exome AF: 0.250

Gnomad NFE exome AF: 0.250

Gnomad OTH exome AF: 0.273

GnomAD4 exome AF: 0.251 AC: 363517 AN: 1449164 Hom.: 48629 Cov.: 57 AF XY: 0.258 AC XY: 185660 AN XY: 719858

Gnomad4 AFR exome AF: 0.0932

Gnomad4 AMR exome AF: 0.196

Gnomad4 ASJ exome AF: 0.390

Gnomad4 EAS exome AF: 0.367

Gnomad4 SAS exome AF: 0.422

Gnomad4 FIN exome AF: 0.245

Gnomad4 NFE exome AF: 0.236

Gnomad4 OTH exome AF: 0.269

GnomAD4 genome AF: 0.214 AC: 32482 AN: 152018 Hom.: 4059 Cov.: 32 AF XY: 0.220 AC XY: 16365 AN XY: 74290

Gnomad4 AFR AF: 0.0977

Gnomad4 AMR AF: 0.207

Gnomad4 ASJ AF: 0.398

Gnomad4 EAS AF: 0.391

Gnomad4 SAS AF: 0.413

Gnomad4 FIN AF: 0.262

Gnomad4 NFE AF: 0.240

Gnomad4 OTH AF: 0.241

Alfa AF: 0.184 Hom.: 638

Bravo AF: 0.206

Asia WGS AF: 0.354 AC: 1228 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neutral lipid storage myopathy Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 25, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.079
Dann	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1135628; hg19: chr11-823809; COSMIC: COSV60744817; COSMIC: COSV60744817;