chr11-819906-G-A

Variant names:

• chr11-819906-G-A
• rs1554975332
• NM_020376.4:c.187+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_020376.4(PNPLA2):​c.187+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000819 in 1,221,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: PNPLA2 NM_020376.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.74
• Publications: 3 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA2	NM_020376.4	c.187+1G>A		splice_donor_variant, intron_variant	Intron 2 of 9	ENST00000336615.9	NP_065109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPLA2	ENST00000336615.9	c.187+1G>A		splice_donor_variant, intron_variant	Intron 2 of 9	1	NM_020376.4	ENSP00000337701.4

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 8.19e-7 AC: 1 AN: 1221608 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 593132

African (AFR) AF: 0.00 AC: 0 AN: 24160

American (AMR) AF: 0.00 AC: 0 AN: 12054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18558

East Asian (EAS) AF: 0.00 AC: 0 AN: 26914

South Asian (SAS) AF: 0.00 AC: 0 AN: 56640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3542

European-Non Finnish (NFE) AF: 0.00000100 AC: 1 AN: 998580

Other (OTH) AF: 0.00 AC: 0 AN: 50152

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		7.7
GERP RS		3.7
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.40		Position offset: -11
DS_DL_spliceai		0.98		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554975332; hg19: chr11-819906;