NM_020376.4:c.187+1G>C

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_020376.4(PNPLA2):​c.187+1G>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000164 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: PNPLA2 NM_020376.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.74
• Publications: 1 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 18 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
• PP5: Variant 11-819906-G-C is Pathogenic according to our data. Variant chr11-819906-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 520846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 0.00000164 AC: 2 AN: 1221608 Hom.: 0 Cov.: 31 AF XY: 0.00000169 AC XY: 1 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: 0.00000200 AC: 2 AN: 998580

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

GnomAD4 genome Cov.: 35

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neutral lipid storage myopathy Pathogenic:2

Sep 25, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 2 of the PNPLA2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PNPLA2 are known to be pathogenic (PMID: 17187067). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with neutral lipid storage disease with myopathy and/or neutral lipid storage disease without myopathy (PMID: 21073837, 33569515). ClinVar contains an entry for this variant (Variation ID: 520846). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Inborn genetic diseases Pathogenic:1

Dec 22, 2015

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.86
PhyloP100		7.7
GERP RS		3.7
Mutation Taster		=0/100	disease causing (ClinVar)

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		0.48		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;