rs150770244

Variant names:

• chr11-824410-G-A
• rs150770244
• NM_020376.4:c.1149G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020376.4(PNPLA2):​c.1149G>A​(p.Arg383Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0074 in 1,554,834 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0075 (59 hom.)
• Consequence: PNPLA2 NM_020376.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.59
• Publications: 3 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=-0.58).
• BP6: Variant 11-824410-G-A is Benign according to our data. Variant chr11-824410-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.6 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00607 (925/152308) while in subpopulation NFE AF = 0.00866 (589/67988). AF 95% confidence interval is 0.00808. There are 3 homozygotes in GnomAd4. There are 449 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.1149G>A	p.Arg383Arg	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.1149G>A	p.Arg383Arg	synonymous	Exon 9 of 10	ENSP00000337701.4	Q96AD5-1
	PNPLA2	ENST00000529255.1	TSL:1	n.579G>A		non_coding_transcript_exon	Exon 3 of 4
	PNPLA2	ENST00000869283.1		c.1533G>A	p.Arg511Arg	synonymous	Exon 10 of 11	ENSP00000539342.1

Frequencies

GnomAD3 genomes AF: 0.00609 AC: 927 AN: 152190 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00762

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00868

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00545 AC: 832 AN: 152654 AF XY: 0.00528

Gnomad AFR exome AF: 0.00118

Gnomad AMR exome AF: 0.00334

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00835

Gnomad NFE exome AF: 0.00771

Gnomad OTH exome AF: 0.00694

GnomAD4 exome AF: 0.00755 AC: 10584 AN: 1402526 Hom.: 59 Cov.: 38 AF XY: 0.00738 AC XY: 5108 AN XY: 692254

African (AFR) AF: 0.00125 AC: 40 AN: 31910

American (AMR) AF: 0.00388 AC: 141 AN: 36312

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 384 AN: 25198

East Asian (EAS) AF: 0.00 AC: 0 AN: 36106

South Asian (SAS) AF: 0.000666 AC: 53 AN: 79542

European-Finnish (FIN) AF: 0.00811 AC: 389 AN: 47952

Middle Eastern (MID) AF: 0.00299 AC: 17 AN: 5688

European-Non Finnish (NFE) AF: 0.00844 AC: 9129 AN: 1081644

Other (OTH) AF: 0.00741 AC: 431 AN: 58174

GnomAD4 genome AF: 0.00607 AC: 925 AN: 152308 Hom.: 3 Cov.: 33 AF XY: 0.00603 AC XY: 449 AN XY: 74488

African (AFR) AF: 0.00140 AC: 58 AN: 41572

American (AMR) AF: 0.00660 AC: 101 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00762 AC: 81 AN: 10630

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00866 AC: 589 AN: 67988

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.00726 Hom.: 2

Bravo AF: 0.00572

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Neutral lipid storage myopathy (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	12
DANN	Benign	0.97
PhyloP100		1.6
Mutation Taster		=100/0	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: rs150770244; hg19: chr11-824410; COSMIC: COSV60745507; COSMIC: COSV60745507;