rs192598547

Variant names:

• chr11-819748-C-T
• rs192598547
• NM_020376.4:c.30C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_020376.4(PNPLA2):​c.30C>T​(p.Ile10Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,508,294 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 35)
  • Exomes 𝑓: 0.0019 (1 hom.)
• Consequence: PNPLA2 NM_020376.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.47
• Publications: 2 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 11-819748-C-T is Benign according to our data. Variant chr11-819748-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 465790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000873 (133/152264) while in subpopulation NFE AF = 0.00169 (115/67996). AF 95% confidence interval is 0.00144. There are 0 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.

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.30C>T	p.Ile10Ile	synonymous	Exon 2 of 10	NP_065109.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA2	ENST00000336615.9	TSL:1 MANE Select	c.30C>T	p.Ile10Ile	synonymous	Exon 2 of 10	ENSP00000337701.4
	PNPLA2	ENST00000869283.1		c.30C>T	p.Ile10Ile	synonymous	Exon 2 of 11	ENSP00000539342.1
	PNPLA2	ENST00000869284.1		c.30C>T	p.Ile10Ile	synonymous	Exon 2 of 10	ENSP00000539343.1

Frequencies

GnomAD3 genomes AF: 0.000881 AC: 134 AN: 152156 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000895 AC: 105 AN: 117292 AF XY: 0.000793

Gnomad AFR exome AF: 0.000807

Gnomad AMR exome AF: 0.000240

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000294

Gnomad NFE exome AF: 0.00206

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.00193 AC: 2622 AN: 1356030 Hom.: 1 Cov.: 32 AF XY: 0.00184 AC XY: 1233 AN XY: 668348

African (AFR) AF: 0.000218 AC: 6 AN: 27530

American (AMR) AF: 0.000280 AC: 9 AN: 32136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23920

East Asian (EAS) AF: 0.00 AC: 0 AN: 29974

South Asian (SAS) AF: 0.00 AC: 0 AN: 75322

European-Finnish (FIN) AF: 0.000502 AC: 23 AN: 45782

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4778

European-Non Finnish (NFE) AF: 0.00237 AC: 2516 AN: 1060736

Other (OTH) AF: 0.00122 AC: 68 AN: 55852

GnomAD4 genome AF: 0.000873 AC: 133 AN: 152264 Hom.: 0 Cov.: 35 AF XY: 0.000779 AC XY: 58 AN XY: 74450

African (AFR) AF: 0.000265 AC: 11 AN: 41574

American (AMR) AF: 0.000131 AC: 2 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

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

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00169 AC: 115 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00136 Hom.: 2

Bravo AF: 0.000865

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	16
DANN	Uncertain	0.98
PhyloP100		2.5
Mutation Taster		=97/3	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: rs192598547; hg19: chr11-819748;