chr18-36796921-T-G

Position:

• chr18-36796921-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015476.4(TPGS2):​c.787A>C​(p.Lys263Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 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: 6.9e-7 (0 hom.)
• Consequence: TPGS2 NM_015476.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88

Genes affected

TPGS2 (HGNC:24561): (tubulin polyglutamylase complex subunit 2) This gene encodes a protein that is a component of the neuronal polyglutamylase complex, which plays a role in post-translational addition of glutamate residues to C-terminal tubulin tails. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2663005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPGS2	NM_015476.4	c.787A>C	p.Lys263Gln	missense_variant	7/7	ENST00000334295.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPGS2	ENST00000334295.9	c.787A>C	p.Lys263Gln	missense_variant	7/7	1	NM_015476.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457622 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725046

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

May 20, 2024

The c.787A>C (p.K263Q) alteration is located in exon 7 (coding exon 7) of the TPGS2 gene. This alteration results from a A to C substitution at nucleotide position 787, causing the lysine (K) at amino acid position 263 to be replaced by a glutamine (Q). 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	0.20
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0051	T;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.9	M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	-1.3	N;.;N
REVEL	Benign	0.13
Sift	Benign	0.15	T;.;T
Sift4G	Benign	0.19	T;T;T
Polyphen		0.99	D;.;D
Vest4		0.23
MutPred		0.28		Loss of methylation at K263 (P = 0.0012);.;.;
MVP		0.71
MPC		0.084
ClinPred		0.59	D
GERP RS		5.9
Varity_R		0.076

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: chr18-34376884;