Genetic Variant NM_021255.3:c.54A>C (chr14-56118714-A-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_021255.3(PELI2):c.54A>C(p.Lys18Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 151,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PELI2
NM_021255.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.00

Publications

3 publications found

Variant links:

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]

PELI2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32103157).

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.54A>C	p.Lys18Asn	missense	Exon 1 of 6	NP_067078.1	Q9HAT8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PELI2	ENST00000267460.9	TSL:1 MANE Select	c.54A>C	p.Lys18Asn	missense	Exon 1 of 6	ENSP00000267460.4	Q9HAT8
PELI2	ENST00000705193.1		c.225A>C	p.Lys75Asn	missense	Exon 1 of 6	ENSP00000516089.1	A0A994J4T1
PELI2	ENST00000559044.5	TSL:4	c.-224+634A>C		intron	N/A	ENSP00000452666.1	H0YK56

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1379076

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

684546

African (AFR)

AF:

0.00

AC:

AN:

28802

American (AMR)

AF:

0.00

AC:

AN:

35310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23600

East Asian (EAS)

AF:

0.00

AC:

AN:

32168

South Asian (SAS)

AF:

0.00

AC:

AN:

78152

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49788

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4600

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1070598

Other (OTH)

AF:

0.00

AC:

AN:

56058

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151208

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73842

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41312

American (AMR)

AF:

0.00

AC:

AN:

15192

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5100

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67732

Other (OTH)

AF:

0.00

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.083

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.83

MetaRNN

Benign

0.32

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.8

PhyloP100

2.0

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.13

Sift

Benign

0.084

Sift4G

Benign

0.15

Polyphen

0.53

Vest4

0.22

MutPred

0.61

Loss of methylation at K18 (P = 0.0054)

MVP

0.12

MPC

1.3

ClinPred

0.98

GERP RS

2.5

PromoterAI

0.058

Neutral

(source)

Varity_R

0.79

gMVP

0.56

Mutation Taster

=71/29

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over