rs759216076
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_173500.4(TTBK2):c.1126C>T(p.Arg376Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,614,048 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
Consequence
NM_173500.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTBK2 | ENST00000267890.11 | c.1126C>T | p.Arg376Cys | missense_variant | Exon 11 of 15 | 5 | NM_173500.4 | ENSP00000267890.6 | ||
TTBK2 | ENST00000567840.5 | c.1126C>T | p.Arg376Cys | missense_variant | Exon 11 of 12 | 1 | ENSP00000455734.1 | |||
TTBK2 | ENST00000567274.5 | c.1021C>T | p.Arg341Cys | missense_variant | Exon 10 of 11 | 5 | ENSP00000457489.1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152060Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249390Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135294
GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461870Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8AN XY: 727236
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74390
ClinVar
Submissions by phenotype
not provided Uncertain:2
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This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 376 of the TTBK2 protein (p.Arg376Cys). This variant is present in population databases (rs759216076, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with TTBK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 586777). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TTBK2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Inborn genetic diseases Uncertain:1
The c.1126C>T (p.R376C) alteration is located in exon 11 (coding exon 10) of the TTBK2 gene. This alteration results from a C to T substitution at nucleotide position 1126, causing the arginine (R) at amino acid position 376 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at