14-56296630-G-T

Variant names:

• chr14-56296630-G-T
• rs368257722
• NM_021255.3:c.727G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_021255.3(PELI2):​c.727G>T​(p.Gly243Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G243S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PELI2 NM_021255.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

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.727G>T	p.Gly243Cys	missense	Exon 6 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.727G>T	p.Gly243Cys	missense	Exon 6 of 6	ENSP00000267460.4	Q9HAT8
	PELI2	ENST00000705193.1		c.898G>T	p.Gly300Cys	missense	Exon 6 of 6	ENSP00000516089.1	A0A994J4T1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457922 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724650

African (AFR) AF: 0.00 AC: 0 AN: 33368

American (AMR) AF: 0.00 AC: 0 AN: 44496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25978

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.00 AC: 0 AN: 86136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109094

Other (OTH) AF: 0.00 AC: 0 AN: 60194

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		10
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.87		Loss of disorder (P = 0.0658)
MVP		0.69
MPC		1.4
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.89
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs368257722; hg19: chr14-56763348;