rs397514625

chr11-823579-A-Cchr11-823579-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_020376.4(PNPLA2):c.749A>C(p.Gln250Pro) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q250R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PNPLA2 NM_020376.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.87

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-823579-A-C is Pathogenic according to our data. Variant chr11-823579-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 39866.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA2	NM_020376.4	c.749A>C	p.Gln250Pro	missense_variant	6/10	ENST00000336615.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA2	ENST00000336615.9	c.749A>C	p.Gln250Pro	missense_variant	6/10	1	NM_020376.4	P1
PNPLA2	ENST00000529255.1	n.37A>C		non_coding_transcript_exon_variant	1/4	1
PNPLA2	ENST00000525250.5	n.1355A>C		non_coding_transcript_exon_variant	4/6	2
PNPLA2	ENST00000531923.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neutral lipid storage myopathy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Uncertain	24
Dann	Benign	0.96
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.044	D
Polyphen		0.30	B
Vest4		0.78
MutPred		0.38		Loss of MoRF binding (P = 0.0473);
MVP		0.50
MPC		0.32
ClinPred		0.31	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs397514625; hg19: chr11-823579;