2-161231167-G-A

Position:

• chr2-161231167-G-A

Variant summary

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

The NM_001199135.3(TANK):​c.717G>A​(p.Met239Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TANK NM_001199135.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84

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]

PSMD14-DT (HGNC:56104): (PSMD14 divergent transcript)

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06960085).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TANK	NM_001199135.3	c.717G>A	p.Met239Ile	missense_variant	7/8	ENST00000392749.7	NP_001186064.1
PSMD14-DT	NR_110593.1	n.349-7684C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TANK	ENST00000392749.7	c.717G>A	p.Met239Ile	missense_variant	7/8	1	NM_001199135.3	ENSP00000376505	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461716 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727142

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000611 Hom.: 0

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

Aug 16, 2022

The c.717G>A (p.M239I) alteration is located in exon 7 (coding exon 6) of the TANK gene. This alteration results from a G to A substitution at nucleotide position 717, causing the methionine (M) at amino acid position 239 to be replaced by an isoleucine (I). 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	0.21
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.15	T;T;T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.85	.;T;D;D
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.070	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L;.;.
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.90	N;N;N;N
REVEL	Benign	0.039
Sift	Benign	0.45	T;T;T;T
Sift4G	Uncertain	0.022	D;D;D;D
Polyphen		0.0050	B;B;.;.
Vest4		0.24
MutPred		0.11		Loss of ubiquitination at K235 (P = 0.0853);Loss of ubiquitination at K235 (P = 0.0853);Loss of ubiquitination at K235 (P = 0.0853);.;
MVP		0.18
MPC		0.33
ClinPred		0.26	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.026
gMVP		0.12

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-162087678;