11-824428-G-T

Variant names:

• chr11-824428-G-T
• rs11554663
• NM_020376.4:c.1167G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020376.4(PNPLA2):​c.1167G>T​(p.Leu389Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0224 in 1,554,754 control chromosomes in the GnomAD database, including 2,084 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (246 hom., cov: 33)
  • Exomes 𝑓: 0.021 (1838 hom.)
• Consequence: PNPLA2 NM_020376.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0150
• Publications: 9 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

ENSG00000255108 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 11-824428-G-T is Benign according to our data. Variant chr11-824428-G-T is described in ClinVar as Benign. ClinVar VariationId is 261231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.015 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

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.1167G>T	p.Leu389Leu	synonymous	Exon 9 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.1167G>T	p.Leu389Leu	synonymous	Exon 9 of 10	ENSP00000337701.4	Q96AD5-1
	PNPLA2	ENST00000529255.1	TSL:1	n.597G>T		non_coding_transcript_exon	Exon 3 of 4
	PNPLA2	ENST00000869283.1		c.1551G>T	p.Leu517Leu	synonymous	Exon 10 of 11	ENSP00000539342.1

Frequencies

GnomAD3 genomes AF: 0.0321 AC: 4886 AN: 152162 Hom.: 246 Cov.: 33

Gnomad AFR AF: 0.0440

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0353

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00727

Gnomad OTH AF: 0.0277

GnomAD2 exomes AF: 0.0470 AC: 7073 AN: 150510 AF XY: 0.0508

Gnomad AFR exome AF: 0.0454

Gnomad AMR exome AF: 0.0148

Gnomad ASJ exome AF: 0.0257

Gnomad EAS exome AF: 0.245

Gnomad FIN exome AF: 0.00197

Gnomad NFE exome AF: 0.00734

Gnomad OTH exome AF: 0.0311

GnomAD4 exome AF: 0.0213 AC: 29899 AN: 1402474 Hom.: 1838 Cov.: 38 AF XY: 0.0240 AC XY: 16587 AN XY: 692332

African (AFR) AF: 0.0454 AC: 1450 AN: 31940

American (AMR) AF: 0.0159 AC: 576 AN: 36298

Ashkenazi Jewish (ASJ) AF: 0.0226 AC: 570 AN: 25200

East Asian (EAS) AF: 0.225 AC: 8123 AN: 36072

South Asian (SAS) AF: 0.119 AC: 9468 AN: 79592

European-Finnish (FIN) AF: 0.00228 AC: 109 AN: 47784

Middle Eastern (MID) AF: 0.0150 AC: 85 AN: 5666

European-Non Finnish (NFE) AF: 0.00690 AC: 7464 AN: 1081738

Other (OTH) AF: 0.0353 AC: 2054 AN: 58184

GnomAD4 genome AF: 0.0322 AC: 4905 AN: 152280 Hom.: 246 Cov.: 33 AF XY: 0.0353 AC XY: 2629 AN XY: 74452

African (AFR) AF: 0.0444 AC: 1844 AN: 41576

American (AMR) AF: 0.0352 AC: 539 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 72 AN: 3472

East Asian (EAS) AF: 0.237 AC: 1225 AN: 5160

South Asian (SAS) AF: 0.131 AC: 633 AN: 4830

European-Finnish (FIN) AF: 0.00311 AC: 33 AN: 10628

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00727 AC: 494 AN: 67988

Other (OTH) AF: 0.0289 AC: 61 AN: 2114

Alfa AF: 0.0200 Hom.: 271

Bravo AF: 0.0320

Asia WGS AF: 0.164 AC: 571 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.9
DANN	Benign	0.73
PhyloP100		-0.015
Mutation Taster		=100/0	polymorphism (auto)

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: rs11554663; hg19: chr11-824428; COSMIC: COSV60744248; COSMIC: COSV60744248;