11-824789-T-C

Variant names:

• chr11-824789-T-C
• rs1138693
• NM_020376.4:c.1442T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000336615.9(PNPLA2):​c.1442T>C​(p.Leu481Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.716 in 1,533,332 control chromosomes in the GnomAD database, including 396,632 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (39382 hom., cov: 35)
  • Exomes 𝑓: 0.72 (357250 hom.)
• Consequence: PNPLA2 ENST00000336615.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.00
• Publications: 48 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, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000255108 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.8413976E-6).
• BP6: Variant 11-824789-T-C is Benign according to our data. Variant chr11-824789-T-C is described in ClinVar as Benign. ClinVar VariationId is 261236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000336615.9. 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.1442T>C	p.Leu481Pro	missense	Exon 10 of 10	NP_065109.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA2	ENST00000336615.9	TSL:1 MANE Select	c.1442T>C	p.Leu481Pro	missense	Exon 10 of 10	ENSP00000337701.4
	PNPLA2	ENST00000529255.1	TSL:1	n.872T>C		non_coding_transcript_exon	Exon 4 of 4
	PNPLA2	ENST00000525250.5	TSL:2	n.2296T>C		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.716 AC: 108843 AN: 151962 Hom.: 39320 Cov.: 35

Gnomad AFR AF: 0.727

Gnomad AMI AF: 0.772

Gnomad AMR AF: 0.751

Gnomad ASJ AF: 0.543

Gnomad EAS AF: 0.619

Gnomad SAS AF: 0.502

Gnomad FIN AF: 0.721

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.733

Gnomad OTH AF: 0.699

GnomAD2 exomes AF: 0.672 AC: 87092 AN: 129622 AF XY: 0.655

Gnomad AFR exome AF: 0.729

Gnomad AMR exome AF: 0.778

Gnomad ASJ exome AF: 0.549

Gnomad EAS exome AF: 0.603

Gnomad FIN exome AF: 0.735

Gnomad NFE exome AF: 0.726

Gnomad OTH exome AF: 0.670

GnomAD4 exome AF: 0.716 AC: 988563 AN: 1381256 Hom.: 357250 Cov.: 58 AF XY: 0.708 AC XY: 482474 AN XY: 681768

African (AFR) AF: 0.729 AC: 22896 AN: 31418

American (AMR) AF: 0.774 AC: 27224 AN: 35176

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 13684 AN: 24894

East Asian (EAS) AF: 0.641 AC: 22900 AN: 35716

South Asian (SAS) AF: 0.491 AC: 38915 AN: 79240

European-Finnish (FIN) AF: 0.737 AC: 24979 AN: 33910

Middle Eastern (MID) AF: 0.559 AC: 3174 AN: 5676

European-Non Finnish (NFE) AF: 0.738 AC: 795103 AN: 1077530

Other (OTH) AF: 0.688 AC: 39688 AN: 57696

GnomAD4 genome AF: 0.716 AC: 108961 AN: 152076 Hom.: 39382 Cov.: 35 AF XY: 0.711 AC XY: 52871 AN XY: 74330

African (AFR) AF: 0.727 AC: 30197 AN: 41514

American (AMR) AF: 0.751 AC: 11485 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.543 AC: 1884 AN: 3472

East Asian (EAS) AF: 0.619 AC: 3188 AN: 5148

South Asian (SAS) AF: 0.503 AC: 2421 AN: 4816

European-Finnish (FIN) AF: 0.721 AC: 7641 AN: 10602

Middle Eastern (MID) AF: 0.575 AC: 168 AN: 292

European-Non Finnish (NFE) AF: 0.733 AC: 49786 AN: 67912

Other (OTH) AF: 0.703 AC: 1487 AN: 2116

Alfa AF: 0.653 Hom.: 3950

Bravo AF: 0.719

TwinsUK AF: 0.749 AC: 2778

ALSPAC AF: 0.740 AC: 2853

ESP6500AA AF: 0.704 AC: 1997

ESP6500EA AF: 0.708 AC: 4530

ExAC AF: 0.579 AC: 46359

Asia WGS AF: 0.599 AC: 2082 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Neutral lipid storage myopathy (4)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Benign	0.080	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0000028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.0
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.67	N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.12	T
Polyphen		0.94	P
Vest4		0.075
MPC		0.36
ClinPred		0.017	T
Varity_R		0.12
gMVP		0.17
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: rs1138693; hg19: chr11-824789; COSMIC: COSV60743886; COSMIC: COSV60743886;