NM_020376.4:c.36C>T

Variant names:

• chr11-819754-C-T
• rs750233571
• NM_020376.4:c.36C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4 BP6 BP7

The NM_020376.4(PNPLA2):​c.36C>T​(p.Phe12Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,509,906 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: PNPLA2 NM_020376.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.02
• 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: Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.14).
• BP6: Variant 11-819754-C-T is Benign according to our data. Variant chr11-819754-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 881329.
• BP7: Synonymous conserved (PhyloP=2.02 with no splicing effect.

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.36C>T	p.Phe12Phe	synonymous	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.36C>T	p.Phe12Phe	synonymous	Exon 2 of 10	ENSP00000337701.4	Q96AD5-1
	PNPLA2	ENST00000869283.1		c.36C>T	p.Phe12Phe	synonymous	Exon 2 of 11	ENSP00000539342.1
	PNPLA2	ENST00000869284.1		c.36C>T	p.Phe12Phe	synonymous	Exon 2 of 10	ENSP00000539343.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152054 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000253 AC: 3 AN: 118724 AF XY: 0.0000302

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000666

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000287 AC: 39 AN: 1357852 Hom.: 0 Cov.: 32 AF XY: 0.0000254 AC XY: 17 AN XY: 669534

African (AFR) AF: 0.00 AC: 0 AN: 27590

American (AMR) AF: 0.00 AC: 0 AN: 32366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23946

East Asian (EAS) AF: 0.00 AC: 0 AN: 30046

South Asian (SAS) AF: 0.00 AC: 0 AN: 75428

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4860

European-Non Finnish (NFE) AF: 0.0000367 AC: 39 AN: 1061742

Other (OTH) AF: 0.00 AC: 0 AN: 55924

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152054 Hom.: 0 Cov.: 35 AF XY: 0.0000269 AC XY: 2 AN XY: 74278

African (AFR) AF: 0.0000241 AC: 1 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000150 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

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	-0.14
CADD	Benign	16
DANN	Uncertain	0.98
PhyloP100		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs750233571; hg19: chr11-819754;