NM_021255.3:c.537C>G

Variant names:

• chr14-56290297-C-G
• rs767570838
• NM_021255.3:c.537C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021255.3(PELI2):​c.537C>G​(p.Asp179Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000375 in 1,599,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: PELI2 NM_021255.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.29
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12671748).

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

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00000811 AC: 2 AN: 246532 AF XY: 0.0000150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000408 AC: 59 AN: 1447624 Hom.: 0 Cov.: 31 AF XY: 0.0000418 AC XY: 30 AN XY: 718294

African (AFR) AF: 0.00 AC: 0 AN: 33164

American (AMR) AF: 0.0000229 AC: 1 AN: 43684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25658

East Asian (EAS) AF: 0.00 AC: 0 AN: 39354

South Asian (SAS) AF: 0.00 AC: 0 AN: 85196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.0000508 AC: 56 AN: 1102070

Other (OTH) AF: 0.0000335 AC: 2 AN: 59676

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000451 Hom.: 0

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	Benign	0.22
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	3.6
DANN	Uncertain	0.98
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.086	N
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		-1.3
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.33
Sift	Benign	0.11	T
Sift4G	Benign	0.089	T
Polyphen		0.94	P
Vest4		0.58
MutPred		0.44		Gain of ubiquitination at K176 (P = 0.1128)
MVP		0.18
MPC		1.1
ClinPred		0.67	D
GERP RS		-9.3
Varity_R		0.50
gMVP		0.34
Mutation Taster		=82/18	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

dbSNP: rs767570838; hg19: chr14-56757015;