chr11-824567-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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. 13/22 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

Clinical Significance

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

Conservation

PhyloP100: 2.21

Publications

2 publications found

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]

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

PNPLA2 links:

ENSG00000255108 (HGNC:):

ENSG00000255108 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017303616).

BP6

Variant 11-824567-C-T is Benign according to our data. Variant chr11-824567-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 306307. Variant chr11-824567-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 306307. Variant chr11-824567-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 306307. Variant chr11-824567-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 306307. Variant chr11-824567-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 306307. Variant chr11-824567-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 306307. Variant chr11-824567-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 306307. Variant chr11-824567-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 306307. Variant chr11-824567-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 306307.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA2	NM_020376.4 link	c.1220C>T	p.Ser407Phe	missense_variant	Exon 10 of 10	ENST00000336615.9	NP_065109.1	Q96AD5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPLA2	ENST00000336615.9 link	c.1220C>T	p.Ser407Phe	missense_variant	Exon 10 of 10	1	NM_020376.4	ENSP00000337701.4		Q96AD5-1

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

185

AN:

152148

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000804

AC:

142

AN:

176510

AF XY:

0.000810

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 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.:

Cov.:

AF XY:

0.00197

AC XY:

1382

AN XY:

703092

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

32854

American (AMR)

AF:

0.000429

AC:

AN:

39602

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25410

East Asian (EAS)

AF:

0.00

AC:

AN:

37868

South Asian (SAS)

AF:

0.0000244

AC:

AN:

82046

European-Finnish (FIN)

AF:

0.000144

AC:

AN:

41658

Middle Eastern (MID)

AF:

0.000181

AC:

AN:

5514

European-Non Finnish (NFE)

AF:

0.00261

AC:

2853

AN:

1094992

Other (OTH)

AF:

0.00161

AC:

AN:

58868

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

190

380

569

759

949

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

122

244

366

488

610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00122

AC:

185

AN:

152258

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.000578

AC:

AN:

41548

American (AMR)

AF:

0.00189

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00187

AC:

127

AN:

68002

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00144

Hom.:

Bravo

AF:

0.00162

ESP6500AA

AF:

0.000467

AC:

ESP6500EA

AF:

0.00155

AC:

ExAC

AF:

0.000461

AC:

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

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4 -

Neutral lipid storage myopathy

Uncertain:1Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Benign

-0.020

Eigen_PC

Benign

-0.094

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.6

PhyloP100

2.2

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.5

REVEL

Benign

0.11

Sift

Uncertain

0.011

Sift4G

Uncertain

0.011

Polyphen

0.97

Vest4

0.17

MVP

0.54

MPC

0.55

ClinPred

0.018

GERP RS

4.0

Varity_R

0.11

gMVP

0.28

Mutation Taster

=70/30

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over