chr2-161231315-G-A

Position:

• chr2-161231315-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001199135.3(TANK):​c.865G>A​(p.Glu289Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,864 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: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TANK NM_001199135.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.74

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19400337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TANK	NM_001199135.3	c.865G>A	p.Glu289Lys	missense_variant	7/8	ENST00000392749.7	NP_001186064.1
PSMD14-DT	NR_110593.1	n.349-7832C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TANK	ENST00000392749.7	c.865G>A	p.Glu289Lys	missense_variant	7/8	1	NM_001199135.3	ENSP00000376505	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

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

Jun 21, 2022

The c.865G>A (p.E289K) 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 865, causing the glutamic acid (E) at amino acid position 289 to be replaced by a lysine (K). 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	0.089
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;T;T;.
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	.;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.19	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;M;.;.;.
MutationTaster	Benign	0.76	D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.7	N;N;N;D;D
REVEL	Benign	0.063
Sift	Uncertain	0.010	D;D;D;D;D
Sift4G	Benign	0.061	T;T;D;D;D
Polyphen		0.75	P;P;.;.;.
Vest4		0.28
MutPred		0.46		Gain of methylation at E289 (P = 0.0053);Gain of methylation at E289 (P = 0.0053);Gain of methylation at E289 (P = 0.0053);.;.;
MVP		0.27
MPC		0.33
ClinPred		0.75	D
GERP RS		3.8
Varity_R		0.088
gMVP		0.48

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: rs1297299378; hg19: chr2-162087826;