11-824528-C-G

Variant names:

• chr11-824528-C-G
• rs373114735
• NM_020376.4:c.1181C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020376.4(PNPLA2):​c.1181C>G​(p.Pro394Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000258 in 1,549,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P394Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PNPLA2 NM_020376.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07237232).

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.1181C>G	p.Pro394Arg	missense	Exon 10 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.1181C>G	p.Pro394Arg	missense	Exon 10 of 10	ENSP00000337701.4	Q96AD5-1
	PNPLA2	ENST00000529255.1	TSL:1	n.611C>G		non_coding_transcript_exon	Exon 4 of 4
	PNPLA2	ENST00000869283.1		c.1565C>G	p.Pro522Arg	missense	Exon 11 of 11	ENSP00000539342.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1397322 Hom.: 0 Cov.: 41 AF XY: 0.00 AC XY: 0 AN XY: 690396

African (AFR) AF: 0.0000312 AC: 1 AN: 32078

American (AMR) AF: 0.00 AC: 0 AN: 36384

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25124

East Asian (EAS) AF: 0.00 AC: 0 AN: 36332

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5400

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082172

Other (OTH) AF: 0.0000172 AC: 1 AN: 58062

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74310

African (AFR) AF: 0.0000241 AC: 1 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Benign	0.86
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.7
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.024
Sift	Benign	0.17	T
Sift4G	Benign	0.37	T
Polyphen		0.37	B
Vest4		0.068
MutPred		0.23		Gain of MoRF binding (P = 0.0039)
MVP		0.22
MPC		0.27
ClinPred		0.086	T
GERP RS		3.3
Varity_R		0.017
gMVP		0.25
Mutation Taster		=92/8	polymorphism

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: rs373114735; hg19: chr11-824528;