rs756590330

Variant names:

• chr15-89665865-C-CCGG
• rs756590330
• NM_002666.5:c.1284_1286dupCCG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_002666.5(PLIN1):​c.1284_1286dupCCG​(p.Arg429dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000621 in 1,503,588 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (1 hom.)
• Consequence: PLIN1 NM_002666.5 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.415
• Publications: 0 publications found

Genes affected

PLIN1 (HGNC:9076): (perilipin 1) The protein encoded by this gene coats lipid storage droplets in adipocytes, thereby protecting them until they can be broken down by hormone-sensitive lipase. The encoded protein is the major cAMP-dependent protein kinase substrate in adipocytes and, when unphosphorylated, may play a role in the inhibition of lipolysis. Alternatively spliced transcript variants varying in the 5' UTR, but encoding the same protein, have been found for this gene. [provided by RefSeq, Feb 2009]

PLIN1 Gene-Disease associations (from GenCC):

• PLIN1-related familial partial lipodystrophy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 15-89665865-C-CCGG is Benign according to our data. Variant chr15-89665865-C-CCGG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3388231.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000513 (78/152002) while in subpopulation NFE AF = 0.000971 (66/67944). AF 95% confidence interval is 0.000783. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 78 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002666.5. 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
	PLIN1	NM_002666.5	MANE Select	c.1284_1286dupCCG	p.Arg429dup	disruptive_inframe_insertion	Exon 9 of 9	NP_002657.3	O60240
	PLIN1	NM_001145311.2		c.1284_1286dupCCG	p.Arg429dup	disruptive_inframe_insertion	Exon 9 of 9	NP_001138783.1	O60240

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLIN1	ENST00000300055.10	TSL:1 MANE Select	c.1284_1286dupCCG	p.Arg429dup	disruptive_inframe_insertion	Exon 9 of 9	ENSP00000300055.5	O60240
	PLIN1	ENST00000896664.1		c.1392_1394dupCCG	p.Arg465dup	disruptive_inframe_insertion	Exon 9 of 9	ENSP00000566723.1
	PLIN1	ENST00000896666.1		c.1314_1316dupCCG	p.Arg439dup	disruptive_inframe_insertion	Exon 9 of 9	ENSP00000566725.1

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 152002 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000971

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000264 AC: 33 AN: 124976 AF XY: 0.000226

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: 0.000602

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000633 AC: 855 AN: 1351586 Hom.: 1 Cov.: 31 AF XY: 0.000588 AC XY: 392 AN XY: 667090

African (AFR) AF: 0.0000705 AC: 2 AN: 28380

American (AMR) AF: 0.0000304 AC: 1 AN: 32874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23906

East Asian (EAS) AF: 0.00 AC: 0 AN: 31840

South Asian (SAS) AF: 0.00 AC: 0 AN: 75342

European-Finnish (FIN) AF: 0.000329 AC: 11 AN: 33394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4976

European-Non Finnish (NFE) AF: 0.000764 AC: 814 AN: 1064818

Other (OTH) AF: 0.000482 AC: 27 AN: 56056

GnomAD4 genome AF: 0.000513 AC: 78 AN: 152002 Hom.: 0 Cov.: 32 AF XY: 0.000485 AC XY: 36 AN XY: 74240

African (AFR) AF: 0.000193 AC: 8 AN: 41434

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000971 AC: 66 AN: 67944

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000348 Hom.: 0

Bravo AF: 0.000412

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	PLIN1-related familial partial lipodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.41
Mutation Taster		=74/26	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs756590330; hg19: chr15-90209096; COSMIC: COSV55583873;