NM_021138.4:c.184C>T

Variant names:

• chr9-136898924-C-T
• rs1211267221
• NM_021138.4:c.184C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021138.4(TRAF2):​c.184C>T​(p.Leu62Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,605,378 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TRAF2 NM_021138.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.68

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26676866).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAF2	NM_021138.4	c.184C>T	p.Leu62Phe	missense_variant	Exon 2 of 11	ENST00000247668.7	NP_066961.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAF2	ENST00000247668.7	c.184C>T	p.Leu62Phe	missense_variant	Exon 2 of 11	1	NM_021138.4	ENSP00000247668.2
TRAF2	ENST00000429509.5	c.184C>T	p.Leu62Phe	missense_variant	Exon 2 of 6	3		ENSP00000406524.1
TRAF2	ENST00000419057.5	c.184C>T	p.Leu62Phe	missense_variant	Exon 3 of 6	3		ENSP00000405860.1
TRAF2	ENST00000414589.1	c.184C>T	p.Leu62Phe	missense_variant	Exon 4 of 6	3		ENSP00000397653.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152152 Hom.: 0 Cov.: 33

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453226 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 722372

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152152 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74312

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.184C>T (p.L62F) alteration is located in exon 2 (coding exon 1) of the TRAF2 gene. This alteration results from a C to T substitution at nucleotide position 184, causing the leucine (L) at amino acid position 62 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	.;.;T;T
Eigen	Benign	-0.097
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.1	.;.;L;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.17	T;T;T;T
Sift4G	Uncertain	0.014	D;D;T;D
Polyphen		0.92	.;.;P;.
Vest4		0.31
MutPred		0.55		Gain of glycosylation at S63 (P = 0.1227);Gain of glycosylation at S63 (P = 0.1227);Gain of glycosylation at S63 (P = 0.1227);Gain of glycosylation at S63 (P = 0.1227);
MVP		0.51
MPC		0.88
ClinPred		0.76	D
GERP RS		-0.56
Varity_R		0.17
gMVP		0.36

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

LitVar

Other links and lift over

dbSNP: rs1211267221; hg19: chr9-139793376;