Genetic Variant PELI2:p.Asp179Glu (chr14-56290297-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_021255.3(PELI2):c.537C>A(p.Asp179Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,599,782 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D179N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

PELI2
NM_021255.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.29

Publications

1 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07923418).

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.537C>A	p.Asp179Glu	missense	Exon 5 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.537C>A	p.Asp179Glu	missense	Exon 5 of 6	ENSP00000267460.4	Q9HAT8
PELI2	ENST00000705193.1		c.708C>A	p.Asp236Glu	missense	Exon 5 of 6	ENSP00000516089.1	A0A994J4T1
PELI2	ENST00000559044.5	TSL:4	c.237C>A	p.Asp79Glu	missense	Exon 5 of 5	ENSP00000452666.1	H0YK56

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000243

AC:

AN:

246532

AF XY:

0.00000751

show subpopulations

Gnomad AFR exome

AF:

0.000371

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000829

AC:

AN:

1447624

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

718294

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

33164

American (AMR)

AF:

0.00

AC:

AN:

43684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25658

East Asian (EAS)

AF:

0.00

AC:

AN:

39354

South Asian (SAS)

AF:

0.00

AC:

AN:

85196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53112

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.00000272

AC:

AN:

1102070

Other (OTH)

AF:

0.0000168

AC:

AN:

59676

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.540

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:

0.0000226

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000247

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.48

CADD

Benign

2.0

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.021

Eigen

Benign

-0.96

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.059

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.014

MetaRNN

Benign

0.079

MetaSVM

Benign

-0.37

MutationAssessor

Uncertain

2.8

PhyloP100

-1.3

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.33

Sift

Benign

0.11

Sift4G

Benign

0.089

Polyphen

0.94

Vest4

0.58

MutPred

0.44

Gain of ubiquitination at K176 (P = 0.1128)

MVP

0.18

MPC

1.1

ClinPred

0.35

GERP RS

-9.3

Varity_R

0.50

gMVP

0.34

Mutation Taster

=82/18

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over