rs28535188

Variant names:

• chr11-819486-T-C
• rs28535188
• NM_020376.4:c.-145-88T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020376.4(PNPLA2):​c.-145-88T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.999 in 1,233,888 control chromosomes in the GnomAD database, including 616,081 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (75988 hom., cov: 37)
  • Exomes 𝑓: 1.0 (540093 hom.)
• Consequence: PNPLA2 NM_020376.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.21
• 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, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 11-819486-T-C is Benign according to our data. Variant chr11-819486-T-C is described in ClinVar as Benign. ClinVar VariationId is 667943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA2	NM_020376.4	MANE Select	c.-145-88T>C		intron	N/A	NP_065109.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA2	ENST00000336615.9	TSL:1 MANE Select	c.-145-88T>C		intron	N/A	ENSP00000337701.4
	PNPLA2	ENST00000869286.1		c.-233T>C		5_prime_UTR	Exon 1 of 9	ENSP00000539345.1
	PNPLA2	ENST00000869283.1		c.-145-88T>C		intron	N/A	ENSP00000539342.1

Frequencies

GnomAD3 genomes AF: 0.999 AC: 152015 AN: 152164 Hom.: 75934 Cov.: 37

Gnomad AFR AF: 1.00

Gnomad AMI AF: 1.00

Gnomad AMR AF: 1.00

Gnomad ASJ AF: 0.974

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.998

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.999

GnomAD4 exome AF: 0.999 AC: 1080895 AN: 1081616 Hom.: 540093 Cov.: 22 AF XY: 0.999 AC XY: 513967 AN XY: 514342

African (AFR) AF: 1.00 AC: 21825 AN: 21826

American (AMR) AF: 1.00 AC: 7228 AN: 7230

Ashkenazi Jewish (ASJ) AF: 0.975 AC: 13437 AN: 13784

East Asian (EAS) AF: 1.00 AC: 23467 AN: 23468

South Asian (SAS) AF: 0.998 AC: 30775 AN: 30840

European-Finnish (FIN) AF: 1.00 AC: 22554 AN: 22556

Middle Eastern (MID) AF: 0.996 AC: 2839 AN: 2850

European-Non Finnish (NFE) AF: 1.00 AC: 915829 AN: 916030

Other (OTH) AF: 0.998 AC: 42941 AN: 43032

GnomAD4 genome AF: 0.999 AC: 152123 AN: 152272 Hom.: 75988 Cov.: 37 AF XY: 0.999 AC XY: 74362 AN XY: 74428

African (AFR) AF: 1.00 AC: 41582 AN: 41584

American (AMR) AF: 1.00 AC: 15304 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.974 AC: 3381 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5148 AN: 5148

South Asian (SAS) AF: 0.998 AC: 4821 AN: 4832

European-Finnish (FIN) AF: 1.00 AC: 10626 AN: 10626

Middle Eastern (MID) AF: 0.986 AC: 288 AN: 292

European-Non Finnish (NFE) AF: 0.999 AC: 67947 AN: 67984

Other (OTH) AF: 0.999 AC: 2114 AN: 2116

Alfa AF: 0.999 Hom.: 9245

Bravo AF: 0.999

Asia WGS AF: 0.998 AC: 3434 AN: 3440

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.6
DANN	Benign	0.69
PhyloP100		-1.2
Mutation Taster		=29/71	disease causing

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: rs28535188; hg19: chr11-819486;