11-819906-G-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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020376.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA2	NM_020376.4	MANE Select	c.187+1G>C		splice_donor intron	N/A	NP_065109.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA2	ENST00000336615.9	TSL:1 MANE Select	c.187+1G>C		splice_donor intron	N/A	ENSP00000337701.4
	PNPLA2	ENST00000869283.1		c.187+1G>C		splice_donor intron	N/A	ENSP00000539342.1
	PNPLA2	ENST00000869284.1		c.187+1G>C		splice_donor intron	N/A	ENSP00000539343.1

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

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Neutral lipid storage myopathy (2)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.97	D
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;