NM_021138.4:c.243C>T

Variant names:

• chr9-136899648-C-T
• rs148192660
• NM_021138.4:c.243C>T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_021138.4(TRAF2):​c.243C>T​(p.Gly81Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00303 in 1,612,882 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (9 hom.)
• Consequence: TRAF2 NM_021138.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.187

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 9-136899648-C-T is Benign according to our data. Variant chr9-136899648-C-T is described in ClinVar as [Benign]. Clinvar id is 719349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.187 with no splicing effect.
• BS2: High AC in GnomAd4 at 296 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAF2	NM_021138.4	c.243C>T	p.Gly81Gly	synonymous_variant	Exon 3 of 11	ENST00000247668.7	NP_066961.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAF2	ENST00000247668.7	c.243C>T	p.Gly81Gly	synonymous_variant	Exon 3 of 11	1	NM_021138.4	ENSP00000247668.2
TRAF2	ENST00000429509.5	c.243C>T	p.Gly81Gly	synonymous_variant	Exon 3 of 6	3		ENSP00000406524.1
TRAF2	ENST00000419057.5	c.243C>T	p.Gly81Gly	synonymous_variant	Exon 4 of 6	3		ENSP00000405860.1
TRAF2	ENST00000414589.1	c.243C>T	p.Gly81Gly	synonymous_variant	Exon 5 of 6	3		ENSP00000397653.1

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 296 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00351

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00224 AC: 562 AN: 251396 Hom.: 0 AF XY: 0.00217 AC XY: 295 AN XY: 135856

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000761

Gnomad SAS exome AF: 0.000980

Gnomad FIN exome AF: 0.00171

Gnomad NFE exome AF: 0.00388

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00314 AC: 4592 AN: 1460610 Hom.: 9 Cov.: 30 AF XY: 0.00305 AC XY: 2216 AN XY: 726540

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.000858

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.00210

Gnomad4 NFE exome AF: 0.00374

Gnomad4 OTH exome AF: 0.00247

GnomAD4 genome AF: 0.00194 AC: 296 AN: 152272 Hom.: 0 Cov.: 33 AF XY: 0.00158 AC XY: 118 AN XY: 74456

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00351

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00291 Hom.: 0

Bravo AF: 0.00195

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 17, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.7
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs148192660; hg19: chr9-139794100;