2-161203511-C-T

Position:

• chr2-161203511-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001199135.3(TANK):​c.124C>T​(p.Arg42Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,458,854 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TANK NM_001199135.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57

Genes affected

TANK (HGNC:11562): (TRAF family member associated NFKB activator) The TRAF (tumor necrosis factor receptor-associated factor) family of proteins associate with and transduce signals from members of the tumor necrosis factor receptor superfamily. The protein encoded by this gene is found in the cytoplasm and can bind to TRAF1, TRAF2, or TRAF3, thereby inhibiting TRAF function by sequestering the TRAFs in a latent state in the cytoplasm. For example, the protein encoded by this gene can block TRAF2 binding to LMP1, the Epstein-Barr virus transforming protein, and inhibit LMP1-mediated NF-kappa-B activation. Three alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22748211).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TANK	NM_001199135.3	c.124C>T	p.Arg42Cys	missense_variant	3/8	ENST00000392749.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TANK	ENST00000392749.7	c.124C>T	p.Arg42Cys	missense_variant	3/8	1	NM_001199135.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1458854 Hom.: 0 Cov.: 30 AF XY: 0.00000827 AC XY: 6 AN XY: 725678

Gnomad4 AFR exome AF: 0.0000599

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2023

The c.124C>T (p.R42C) alteration is located in exon 3 (coding exon 2) of the TANK gene. This alteration results from a C to T substitution at nucleotide position 124, causing the arginine (R) at amino acid position 42 to be replaced by a cysteine (C). 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	Benign	0.16
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T;T;T;T;T;T;.;T;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.94	.;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.;L;.;.;.;.;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.0	D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.14
Sift	Benign	0.047	D;T;D;T;D;D;D;D;T;T
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.
Vest4		0.26
MutPred		0.18		Loss of solvent accessibility (P = 0.2517);.;Loss of solvent accessibility (P = 0.2517);Loss of solvent accessibility (P = 0.2517);.;.;.;Loss of solvent accessibility (P = 0.2517);.;Loss of solvent accessibility (P = 0.2517);
MVP		0.34
MPC		1.2
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.13

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: rs1238769499; hg19: chr2-162060022; COSMIC: COSV52043642;