rs538014722

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_020376.4(PNPLA2):​c.661C>A​(p.Arg221Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PNPLA2
NM_020376.4 missense

Scores

7
9
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.40
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PNPLA2NM_020376.4 linkc.661C>A p.Arg221Ser missense_variant Exon 5 of 10 ENST00000336615.9 NP_065109.1 Q96AD5-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PNPLA2ENST00000336615.9 linkc.661C>A p.Arg221Ser missense_variant Exon 5 of 10 1 NM_020376.4 ENSP00000337701.4 Q96AD5-1
PNPLA2ENST00000525250.5 linkn.1267C>A non_coding_transcript_exon_variant Exon 3 of 6 2
PNPLA2ENST00000531923.1 linkn.556C>A non_coding_transcript_exon_variant Exon 1 of 2 2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461618
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727124
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.74
D
Eigen
Uncertain
0.32
Eigen_PC
Benign
0.13
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Uncertain
0.96
D
M_CAP
Pathogenic
0.45
D
MetaRNN
Pathogenic
0.90
D
MetaSVM
Uncertain
0.38
D
MutationAssessor
Pathogenic
3.0
M
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-3.0
D
REVEL
Pathogenic
0.66
Sift
Benign
0.042
D
Sift4G
Uncertain
0.022
D
Polyphen
1.0
D
Vest4
0.94
MutPred
0.53
Loss of MoRF binding (P = 0.0168);
MVP
0.89
MPC
0.89
ClinPred
0.99
D
GERP RS
2.1
Varity_R
0.54
gMVP
0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-822571; API