rs202081894

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_020376.4(PNPLA2):​c.1220C>T​(p.Ser407Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,571,070 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0021 ( 6 hom. )

Consequence

PNPLA2
NM_020376.4 missense

Scores

5
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 2.21
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.017303616).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00122 (185/152258) while in subpopulation AMR AF= 0.00189 (29/15304). AF 95% confidence interval is 0.0016. There are 1 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PNPLA2NM_020376.4 linkuse as main transcriptc.1220C>T p.Ser407Phe missense_variant 10/10 ENST00000336615.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PNPLA2ENST00000336615.9 linkuse as main transcriptc.1220C>T p.Ser407Phe missense_variant 10/101 NM_020376.4 P1Q96AD5-1
ENST00000532946.1 linkuse as main transcriptn.307-704G>A intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
AF:
0.00122
AC:
185
AN:
152148
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000579
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00190
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00187
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.000804
AC:
142
AN:
176510
Hom.:
0
AF XY:
0.000810
AC XY:
79
AN XY:
97486
show subpopulations
Gnomad AFR exome
AF:
0.000502
Gnomad AMR exome
AF:
0.0000701
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000390
Gnomad FIN exome
AF:
0.000185
Gnomad NFE exome
AF:
0.00174
Gnomad OTH exome
AF:
0.000631
GnomAD4 exome
AF:
0.00211
AC:
2989
AN:
1418812
Hom.:
6
Cov.:
42
AF XY:
0.00197
AC XY:
1382
AN XY:
703092
show subpopulations
Gnomad4 AFR exome
AF:
0.000457
Gnomad4 AMR exome
AF:
0.000429
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000244
Gnomad4 FIN exome
AF:
0.000144
Gnomad4 NFE exome
AF:
0.00261
Gnomad4 OTH exome
AF:
0.00161
GnomAD4 genome
AF:
0.00122
AC:
185
AN:
152258
Hom.:
1
Cov.:
33
AF XY:
0.00113
AC XY:
84
AN XY:
74434
show subpopulations
Gnomad4 AFR
AF:
0.000578
Gnomad4 AMR
AF:
0.00189
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00187
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.00146
Hom.:
0
Bravo
AF:
0.00162
ESP6500AA
AF:
0.000467
AC:
2
ESP6500EA
AF:
0.00155
AC:
13
ExAC
AF:
0.000461
AC:
54

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJan 12, 2023BP4 -
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2023- -
Neutral lipid storage myopathy Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.37
T
Eigen
Benign
-0.020
Eigen_PC
Benign
-0.094
FATHMM_MKL
Benign
0.61
D
LIST_S2
Benign
0.79
T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.017
T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
1.6
L
MutationTaster
Benign
0.61
D
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-1.5
N
REVEL
Benign
0.11
Sift
Uncertain
0.011
D
Sift4G
Uncertain
0.011
D
Polyphen
0.97
D
Vest4
0.17
MVP
0.54
MPC
0.55
ClinPred
0.018
T
GERP RS
4.0
Varity_R
0.11
gMVP
0.28

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs202081894; hg19: chr11-824567; COSMIC: COSV60744522; COSMIC: COSV60744522; API