11-823809-C-G

Variant names:

• chr11-823809-C-G
• rs1135628
• NM_020376.4:c.873C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020376.4(PNPLA2):​c.873C>G​(p.Pro291Pro) 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:6
• Conservation: PhyloP100: -2.58
• Publications: 22 publications found

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

ENSG00000255108 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 261248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.873C>G	p.Pro291Pro	synonymous	Exon 7 of 10	NP_065109.1	Q96AD5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA2	ENST00000336615.9	TSL:1 MANE Select	c.873C>G	p.Pro291Pro	synonymous	Exon 7 of 10	ENSP00000337701.4	Q96AD5-1
	PNPLA2	ENST00000529255.1	TSL:1	n.161C>G		non_coding_transcript_exon	Exon 2 of 4
	PNPLA2	ENST00000869283.1		c.1257C>G	p.Pro419Pro	synonymous	Exon 8 of 11	ENSP00000539342.1

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

GnomAD2 exomes AF: 0.273 AC: 60745 AN: 222352 AF XY: 0.289

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 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

African (AFR) AF: 0.0932 AC: 3105 AN: 33302

American (AMR) AF: 0.196 AC: 8478 AN: 43362

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 10073 AN: 25848

East Asian (EAS) AF: 0.367 AC: 14375 AN: 39190

South Asian (SAS) AF: 0.422 AC: 35748 AN: 84784

European-Finnish (FIN) AF: 0.245 AC: 12340 AN: 50284

Middle Eastern (MID) AF: 0.376 AC: 2160 AN: 5750

European-Non Finnish (NFE) AF: 0.236 AC: 261129 AN: 1106736

Other (OTH) AF: 0.269 AC: 16109 AN: 59908

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

African (AFR) AF: 0.0977 AC: 4055 AN: 41494

American (AMR) AF: 0.207 AC: 3164 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 1383 AN: 3472

East Asian (EAS) AF: 0.391 AC: 2013 AN: 5146

South Asian (SAS) AF: 0.413 AC: 1994 AN: 4830

European-Finnish (FIN) AF: 0.262 AC: 2764 AN: 10560

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.240 AC: 16299 AN: 67916

Other (OTH) AF: 0.241 AC: 509 AN: 2108

Alfa AF: 0.184 Hom.: 638

Bravo AF: 0.206

Asia WGS AF: 0.354 AC: 1228 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Neutral lipid storage myopathy (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.079
DANN	Benign	0.70
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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