chr15-89665828-C-A

Variant names:

• chr15-89665828-C-A
• rs1446833198
• NM_002666.5:c.1324G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002666.5(PLIN1):​c.1324G>T​(p.Gly442Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000079 in 1,265,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G442S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: PLIN1 NM_002666.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.19
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039651275).

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.1324G>T	p.Gly442Cys	missense	Exon 9 of 9	NP_002657.3	O60240
	PLIN1	NM_001145311.2		c.1324G>T	p.Gly442Cys	missense	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.1324G>T	p.Gly442Cys	missense	Exon 9 of 9	ENSP00000300055.5	O60240
	PLIN1	ENST00000896664.1		c.1432G>T	p.Gly478Cys	missense	Exon 9 of 9	ENSP00000566723.1
	PLIN1	ENST00000896666.1		c.1354G>T	p.Gly452Cys	missense	Exon 9 of 9	ENSP00000566725.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.90e-7 AC: 1 AN: 1265676 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 618710

African (AFR) AF: 0.00 AC: 0 AN: 25942

American (AMR) AF: 0.0000418 AC: 1 AN: 23924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21152

East Asian (EAS) AF: 0.00 AC: 0 AN: 27886

South Asian (SAS) AF: 0.00 AC: 0 AN: 64934

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3996

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1016300

Other (OTH) AF: 0.00 AC: 0 AN: 51830

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.82
DANN	Benign	0.88
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.55	N
PhyloP100		-3.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.018
Sift	Benign	0.18	T
Sift4G	Benign	0.16	T
Polyphen		0.0010	B
Vest4		0.11
MutPred		0.21		Loss of MoRF binding (P = 0.1085)
MVP		0.040
MPC		1.3
ClinPred		0.066	T
GERP RS		-8.9
Varity_R		0.088
gMVP		0.082
Mutation Taster		=96/4	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: rs1446833198; hg19: chr15-90209059;