14-56118733-C-A

Variant names:

• chr14-56118733-C-A
• NM_021255.3:c.73C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021255.3(PELI2):​c.73C>A​(p.Leu25Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000947 in 1,372,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000095 (0 hom.)
• Consequence: PELI2 NM_021255.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19
• Publications: 0 publications found

Genes affected

PELI2 (HGNC:8828): (pellino E3 ubiquitin protein ligase family member 2) Predicted to enable protein-macromolecule adaptor activity and ubiquitin protein ligase activity. Acts upstream of or within positive regulation of MAPK cascade and positive regulation of protein phosphorylation. Predicted to be located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021255.3. 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
	PELI2	NM_021255.3	MANE Select	c.73C>A	p.Leu25Ile	missense	Exon 1 of 6	NP_067078.1	Q9HAT8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PELI2	ENST00000267460.9	TSL:1 MANE Select	c.73C>A	p.Leu25Ile	missense	Exon 1 of 6	ENSP00000267460.4	Q9HAT8
	PELI2	ENST00000705193.1		c.244C>A	p.Leu82Ile	missense	Exon 1 of 6	ENSP00000516089.1	A0A994J4T1
	PELI2	ENST00000559044.5	TSL:4	c.-224+653C>A		intron	N/A	ENSP00000452666.1	H0YK56

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000947 AC: 13 AN: 1372720 Hom.: 0 Cov.: 28 AF XY: 0.00000294 AC XY: 2 AN XY: 681064

African (AFR) AF: 0.00 AC: 0 AN: 28760

American (AMR) AF: 0.00 AC: 0 AN: 34870

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23526

East Asian (EAS) AF: 0.00 AC: 0 AN: 31986

South Asian (SAS) AF: 0.00 AC: 0 AN: 77614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4538

European-Non Finnish (NFE) AF: 0.0000113 AC: 12 AN: 1066160

Other (OTH) AF: 0.0000180 AC: 1 AN: 55666

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

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	Pathogenic	0.68
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.099
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.35	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		1.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.32
Sift	Benign	0.064	T
Sift4G	Benign	0.14	T
Polyphen		0.94	P
Vest4		0.31
MutPred		0.81		Loss of disorder (P = 0.0891)
MVP		0.33
MPC		1.4
ClinPred		0.98	D
GERP RS		2.8
PromoterAI		0.14	Neutral
Varity_R		0.45
gMVP		0.31
Mutation Taster		=80/20	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

hg19: chr14-56585451;