Genetic Variant TRAF2:p.Cys124Tyr (chr9-136908074-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021138.4(TRAF2):c.371G>A(p.Cys124Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. C124F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TRAF2
NM_021138.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.09

Publications

0 publications found

Variant links:

Genes affected

TRAF2 (HGNC:12032): (TNF receptor associated factor 2) The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins associate with, and mediate the signal transduction from members of the TNF receptor superfamily. This protein directly interacts with TNF receptors, and forms a heterodimeric complex with TRAF1. This protein is required for TNF-alpha-mediated activation of MAPK8/JNK and NF-kappaB. The protein complex formed by this protein and TRAF1 interacts with the inhibitor-of-apoptosis proteins (IAPs), and functions as a mediator of the anti-apoptotic signals from TNF receptors. The interaction of this protein with TRADD, a TNF receptor associated apoptotic signal transducer, ensures the recruitment of IAPs for the direct inhibition of caspase activation. BIRC2/c-IAP1, an apoptosis inhibitor possessing ubiquitin ligase activity, can unbiquitinate and induce the degradation of this protein, and thus potentiate TNF-induced apoptosis. Multiple alternatively spliced transcript variants have been found for this gene, but the biological validity of only one transcript has been determined. [provided by RefSeq, Jul 2008]

TRAF2 links:

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ACMG classification

Classification was made for transcript

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=0.17833889).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021138.4. 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
	TRAF2	NM_021138.4	MANE Select	c.371G>A	p.Cys124Tyr	missense	Exon 5 of 11	NP_066961.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRAF2	ENST00000247668.7	TSL:1 MANE Select	c.371G>A	p.Cys124Tyr	missense	Exon 5 of 11	ENSP00000247668.2	Q12933-1
TRAF2	ENST00000882556.1		c.527G>A	p.Cys176Tyr	missense	Exon 5 of 11	ENSP00000552615.1
TRAF2	ENST00000882557.1		c.371G>A	p.Cys124Tyr	missense	Exon 5 of 11	ENSP00000552616.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1448356

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721032

African (AFR)

AF:

0.00

AC:

AN:

33216

American (AMR)

AF:

0.00

AC:

AN:

43338

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25854

East Asian (EAS)

AF:

0.00

AC:

AN:

39656

South Asian (SAS)

AF:

0.00

AC:

AN:

85788

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110034

Other (OTH)

AF:

0.00

AC:

AN:

60112

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.20

Eigen

Benign

0.12

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.82

M_CAP

Benign

0.014

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PhyloP100

2.1

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.068

Sift

Benign

0.068

Sift4G

Benign

0.097

Polyphen

0.40

Vest4

0.34

MutPred

0.29

Loss of helix (P = 0.028)

MVP

0.22

MPC

0.42

ClinPred

0.81

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.41

gMVP

0.78

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over