3-9867295-C-T

Variant names:

• chr3-9867295-C-T
• rs587776968
• NM_001321142.2:c.556G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001321142.2(CIDEC):​c.556G>A​(p.Glu186Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CIDEC NM_001321142.2 missense, splice_region
• Scores: Splicing: ADA: 0.9890
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.33
• Publications: 0 publications found

Genes affected

CIDEC (HGNC:24229): (cell death inducing DFFA like effector c) This gene encodes a member of the cell death-inducing DNA fragmentation factor-like effector family. Members of this family play important roles in apoptosis. The encoded protein promotes lipid droplet formation in adipocytes and may mediate adipocyte apoptosis. This gene is regulated by insulin and its expression is positively correlated with insulin sensitivity. Mutations in this gene may contribute to insulin resistant diabetes. A pseudogene of this gene is located on the short arm of chromosome 3. Alternatively spliced transcript variants that encode different isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

CIDEC Gene-Disease associations (from GenCC):

• CIDEC-related familial partial lipodystrophy

  Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000308530 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321142.2. 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
	CIDEC	NM_001321142.2	MANE Select	c.556G>A	p.Glu186Lys	missense splice_region	Exon 7 of 7	NP_001308071.1	Q96AQ7-1
	CIDEC	NM_001199623.2		c.595G>A	p.Glu199Lys	missense splice_region	Exon 6 of 6	NP_001186552.1	A0A0A0MRY9
	CIDEC	NM_001199551.2		c.586G>A	p.Glu196Lys	missense splice_region	Exon 7 of 7	NP_001186480.1	Q96AQ7-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIDEC	ENST00000336832.7	TSL:1 MANE Select	c.556G>A	p.Glu186Lys	missense splice_region	Exon 7 of 7	ENSP00000338642.2	Q96AQ7-1
	CIDEC	ENST00000383817.5	TSL:1	c.595G>A	p.Glu199Lys	missense splice_region	Exon 6 of 6	ENSP00000373328.2	A0A0A0MRY9
	CIDEC	ENST00000455015.6	TSL:1	c.334G>A	p.Glu112Lys	missense splice_region	Exon 6 of 6	ENSP00000392975.1	Q96AQ7-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461732 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727150

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.3
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.67
Sift	Benign	0.074	T
Sift4G	Benign	0.078	T
Polyphen		1.0	D
Vest4		0.85
MutPred		0.42		Gain of MoRF binding (P = 0.0056)
MVP		0.95
MPC		0.056
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.27
gMVP		0.75
Mutation Taster		=21/79	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		0.050		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: rs587776968; hg19: chr3-9908979;