11-819601-C-T

Position:

• chr11-819601-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_020376.4(PNPLA2):​c.-118C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000705 in 1,279,430 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00075 (1 hom.)
• Consequence: PNPLA2 NM_020376.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -3.06

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000401 (61/152176) while in subpopulation NFE AF= 0.000632 (43/68024). AF 95% confidence interval is 0.000482. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPLA2	NM_020376.4	c.-118C>T		5_prime_UTR_premature_start_codon_gain_variant	2/10	ENST00000336615.9	NP_065109.1
PNPLA2	NM_020376.4	c.-118C>T		5_prime_UTR_variant	2/10	ENST00000336615.9	NP_065109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPLA2	ENST00000336615	c.-118C>T		5_prime_UTR_premature_start_codon_gain_variant	2/10	1	NM_020376.4	ENSP00000337701.4
PNPLA2	ENST00000336615	c.-118C>T		5_prime_UTR_variant	2/10	1	NM_020376.4	ENSP00000337701.4

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152176 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000746 AC: 841 AN: 1127254 Hom.: 1 Cov.: 18 AF XY: 0.000771 AC XY: 420 AN XY: 544432

Gnomad4 AFR exome AF: 0.000135

Gnomad4 AMR exome AF: 0.000353

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000351

Gnomad4 FIN exome AF: 0.000392

Gnomad4 NFE exome AF: 0.000830

Gnomad4 OTH exome AF: 0.000734

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152176 Hom.: 0 Cov.: 35 AF XY: 0.000404 AC XY: 30 AN XY: 74348

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000530 Hom.: 0

Bravo AF: 0.000427

Asia WGS AF: 0.000290 AC: 1 AN: 3462

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neutral lipid storage myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.45
DANN	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs769594766; hg19: chr11-819601;