rs765640246

Positions:

• chr11-824762-C-A
• chr11-824762-C-G
• chr11-824762-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020376.4(PNPLA2):​c.1415C>A​(p.Ala472Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,403,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. A472G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PNPLA2 NM_020376.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.106

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053414702).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA2	NM_020376.4	c.1415C>A	p.Ala472Glu	missense_variant	10/10	ENST00000336615.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA2	ENST00000336615.9	c.1415C>A	p.Ala472Glu	missense_variant	10/10	1	NM_020376.4	P1
PNPLA2	ENST00000529255.1	n.845C>A		non_coding_transcript_exon_variant	4/4	1
	ENST00000532946.1	n.307-899G>T		intron_variant, non_coding_transcript_variant		5
PNPLA2	ENST00000525250.5	n.2269C>A		non_coding_transcript_exon_variant	6/6	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000131 AC: 2 AN: 152416 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 84588

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000374

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000161

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1403748 Hom.: 0 Cov.: 42 AF XY: 0.00000144 AC XY: 1 AN XY: 694992

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000259

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000184 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.9
DANN	Benign	0.77
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.036
Sift	Benign	0.043	D
Sift4G	Benign	1.0	T
Polyphen		0.078	B
Vest4		0.13
MutPred		0.071		Gain of solvent accessibility (P = 0.0456);
MVP		0.092
MPC		0.26
ClinPred		0.027	T
GERP RS		-0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.097
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs765640246; hg19: chr11-824762;