11-821809-C-T

Variant names:

• chr11-821809-C-T
• rs142174851
• NM_020376.4:c.369C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_020376.4(PNPLA2):​c.369C>T​(p.Asp123Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000652 in 1,613,964 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00065 (2 hom.)
• Consequence: PNPLA2 NM_020376.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.34
• Publications: 2 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, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 11-821809-C-T is Benign according to our data. Variant chr11-821809-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261241.
• BP7: Synonymous conserved (PhyloP=-1.34 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00067 (102/152328) while in subpopulation AMR AF = 0.00281 (43/15300). AF 95% confidence interval is 0.00214. There are 0 homozygotes in GnomAd4. There are 46 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.369C>T	p.Asp123Asp	synonymous	Exon 3 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.369C>T	p.Asp123Asp	synonymous	Exon 3 of 10	ENSP00000337701.4	Q96AD5-1
	PNPLA2	ENST00000869283.1		c.753C>T	p.Asp251Asp	synonymous	Exon 4 of 11	ENSP00000539342.1
	PNPLA2	ENST00000869284.1		c.369C>T	p.Asp123Asp	synonymous	Exon 3 of 10	ENSP00000539343.1

Frequencies

GnomAD3 genomes AF: 0.000670 AC: 102 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000692 AC: 174 AN: 251298 AF XY: 0.000714

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000660

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.000651 AC: 951 AN: 1461636 Hom.: 2 Cov.: 32 AF XY: 0.000648 AC XY: 471 AN XY: 727104

African (AFR) AF: 0.000179 AC: 6 AN: 33478

American (AMR) AF: 0.00224 AC: 100 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86256

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000710 AC: 790 AN: 1111998

Other (OTH) AF: 0.000530 AC: 32 AN: 60390

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000618 AC XY: 46 AN XY: 74492

African (AFR) AF: 0.000168 AC: 7 AN: 41570

American (AMR) AF: 0.00281 AC: 43 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68034

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000693 Hom.: 0

Bravo AF: 0.000945

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Neutral lipid storage myopathy (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	1.8
DANN	Benign	0.91
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

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: rs142174851; hg19: chr11-821809; COSMIC: COSV60744571; COSMIC: COSV60744571;