NM_020376.4:c.-19C>A

Variant names:

• chr11-819700-C-A
• rs550469869
• NM_020376.4:c.-19C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_020376.4(PNPLA2):​c.-19C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000332 in 1,476,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: PNPLA2 NM_020376.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.533
• 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: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 11-819700-C-A is Benign according to our data. Variant chr11-819700-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 306293.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000138 (21/152260) while in subpopulation EAS AF = 0.00386 (20/5176). AF 95% confidence interval is 0.00256. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.

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.-19C>A		5_prime_UTR	Exon 2 of 10	NP_065109.1	Q96AD5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA2	ENST00000336615.9	TSL:1 MANE Select	c.-19C>A		5_prime_UTR	Exon 2 of 10	ENSP00000337701.4	Q96AD5-1
	PNPLA2	ENST00000869283.1		c.-19C>A		5_prime_UTR	Exon 2 of 11	ENSP00000539342.1
	PNPLA2	ENST00000869284.1		c.-19C>A		5_prime_UTR	Exon 2 of 10	ENSP00000539343.1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152152 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000188 AC: 16 AN: 85282 AF XY: 0.000206

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00484

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000211 AC: 28 AN: 1324550 Hom.: 0 Cov.: 31 AF XY: 0.0000184 AC XY: 12 AN XY: 651228

African (AFR) AF: 0.00 AC: 0 AN: 26734

American (AMR) AF: 0.00 AC: 0 AN: 27278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23386

East Asian (EAS) AF: 0.000886 AC: 25 AN: 28226

South Asian (SAS) AF: 0.0000137 AC: 1 AN: 73138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3992

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1046798

Other (OTH) AF: 0.0000367 AC: 2 AN: 54510

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152260 Hom.: 0 Cov.: 35 AF XY: 0.000134 AC XY: 10 AN XY: 74458

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00386 AC: 20 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000125

Asia WGS AF: 0.000293 AC: 1 AN: 3424

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Neutral lipid storage myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.6
DANN	Benign	0.92
PhyloP100		0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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

Other links and lift over

dbSNP: rs550469869; hg19: chr11-819700;