rs148314086

Variant names:

• chr11-823859-C-T
• rs148314086
• NM_020376.4:c.919+4C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020376.4(PNPLA2):​c.919+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00535 in 1,580,874 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0054 (31 hom.)
• Consequence: PNPLA2 NM_020376.4 splice_region, intron
• Scores: Splicing: ADA: 0.003239
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.93
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 11-823859-C-T is Benign according to our data. Variant chr11-823859-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00475 (723/152156) while in subpopulation NFE AF = 0.00577 (392/67970). AF 95% confidence interval is 0.0053. There are 5 homozygotes in GnomAd4. There are 396 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.919+4C>T		splice_region intron	N/A	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.919+4C>T		splice_region intron	N/A	ENSP00000337701.4	Q96AD5-1
	PNPLA2	ENST00000529255.1	TSL:1	n.211C>T		non_coding_transcript_exon	Exon 2 of 4
	PNPLA2	ENST00000869283.1		c.1303+4C>T		splice_region intron	N/A	ENSP00000539342.1

Frequencies

GnomAD3 genomes AF: 0.00476 AC: 723 AN: 152040 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0227

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00577

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00448 AC: 836 AN: 186414 AF XY: 0.00438

Gnomad AFR exome AF: 0.000688

Gnomad AMR exome AF: 0.000383

Gnomad ASJ exome AF: 0.00695

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0215

Gnomad NFE exome AF: 0.00523

Gnomad OTH exome AF: 0.00382

GnomAD4 exome AF: 0.00541 AC: 7727 AN: 1428718 Hom.: 31 Cov.: 38 AF XY: 0.00526 AC XY: 3728 AN XY: 708170

African (AFR) AF: 0.000701 AC: 23 AN: 32826

American (AMR) AF: 0.000348 AC: 14 AN: 40206

Ashkenazi Jewish (ASJ) AF: 0.00611 AC: 156 AN: 25544

East Asian (EAS) AF: 0.00 AC: 0 AN: 38160

South Asian (SAS) AF: 0.00 AC: 0 AN: 82648

European-Finnish (FIN) AF: 0.0217 AC: 1031 AN: 47506

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5724

European-Non Finnish (NFE) AF: 0.00572 AC: 6276 AN: 1096858

Other (OTH) AF: 0.00381 AC: 226 AN: 59246

GnomAD4 genome AF: 0.00475 AC: 723 AN: 152156 Hom.: 5 Cov.: 33 AF XY: 0.00532 AC XY: 396 AN XY: 74392

African (AFR) AF: 0.000819 AC: 34 AN: 41530

American (AMR) AF: 0.000588 AC: 9 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00951 AC: 33 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.0227 AC: 241 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00577 AC: 392 AN: 67970

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00457 Hom.: 1

Bravo AF: 0.00284

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Neutral lipid storage myopathy (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.0080
DANN	Benign	0.88
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0032
dbscSNV1_RF	Benign	0.10
SpliceAI score (max)		0.070		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: rs148314086; hg19: chr11-823859;