11-823582-G-C

Variant names:

• chr11-823582-G-C
• rs988744471
• NM_020376.4:c.752G>C

Variant summary

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

The NM_020376.4(PNPLA2):​c.752G>C​(p.Arg251Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R251Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PNPLA2 NM_020376.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA2	NM_020376.4	MANE Select	c.752G>C	p.Arg251Pro	missense	Exon 6 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.752G>C	p.Arg251Pro	missense	Exon 6 of 10	ENSP00000337701.4
	PNPLA2	ENST00000529255.1	TSL:1	n.40G>C		non_coding_transcript_exon	Exon 1 of 4
	PNPLA2	ENST00000525250.5	TSL:2	n.1358G>C		non_coding_transcript_exon	Exon 4 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.752G>C (p.R251P) alteration is located in exon 6 (coding exon 5) of the PNPLA2 gene. This alteration results from a G to C substitution at nucleotide position 752, causing the arginine (R) at amino acid position 251 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.057	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.025	D
Polyphen		0.91	P
Vest4		0.74
MutPred		0.40		Loss of MoRF binding (P = 0.0031)
MVP		0.75
MPC		0.81
ClinPred		0.88	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.82
Mutation Taster		=54/46	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: rs988744471; hg19: chr11-823582;