chr11-821839-C-T

Variant names:

• chr11-821839-C-T
• rs143992505
• NM_020376.4:c.399C>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.399C>T​(p.Asn133Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000375 in 1,613,926 control chromosomes in the GnomAD database, including 3 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 0.00055 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (2 hom.)
• Consequence: PNPLA2 NM_020376.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.25
• 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, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 11-821839-C-T is Benign according to our data. Variant chr11-821839-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 306295.
• BP7: Synonymous conserved (PhyloP=1.25 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000551 (84/152364) while in subpopulation AFR AF = 0.000625 (26/41580). AF 95% confidence interval is 0.000438. There are 1 homozygotes in GnomAd4. There are 37 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.399C>T	p.Asn133Asn	synonymous	Exon 3 of 10	NP_065109.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA2	ENST00000336615.9	TSL:1 MANE Select	c.399C>T	p.Asn133Asn	synonymous	Exon 3 of 10	ENSP00000337701.4
	PNPLA2	ENST00000869283.1		c.783C>T	p.Asn261Asn	synonymous	Exon 4 of 11	ENSP00000539342.1
	PNPLA2	ENST00000869284.1		c.399C>T	p.Asn133Asn	synonymous	Exon 3 of 10	ENSP00000539343.1

Frequencies

GnomAD3 genomes AF: 0.000545 AC: 83 AN: 152246 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000756 AC: 190 AN: 251240 AF XY: 0.000685

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.0100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.000356 AC: 521 AN: 1461562 Hom.: 2 Cov.: 32 AF XY: 0.000362 AC XY: 263 AN XY: 727078

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.00150 AC: 67 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0106 AC: 276 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.000132 AC: 7 AN: 53170

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000854 AC: 95 AN: 1111946

Other (OTH) AF: 0.000911 AC: 55 AN: 60384

GnomAD4 genome AF: 0.000551 AC: 84 AN: 152364 Hom.: 1 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74512

African (AFR) AF: 0.000625 AC: 26 AN: 41580

American (AMR) AF: 0.000131 AC: 2 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3472

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

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

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68038

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00120 Hom.: 1

Bravo AF: 0.000676

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	9.8
DANN	Benign	0.96
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs143992505; hg19: chr11-821839;