Genetic Variant TUBG2:p.Arg296Trp (chr17-42666129-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_016437.3(TUBG2):c.886C>T(p.Arg296Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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

TUBG2
NM_016437.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.618

Publications

0 publications found

Variant links:

Genes affected

TUBG2 (HGNC:12419): (tubulin gamma 2) Predicted to enable GTP binding activity. Predicted to be a structural constituent of cytoskeleton. Predicted to be involved in microtubule cytoskeleton organization and mitotic sister chromatid segregation. Located in microtubule. [provided by Alliance of Genome Resources, Apr 2022]

TUBG2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBG2	NM_016437.3 link	c.886C>T	p.Arg296Trp	missense_variant	Exon 9 of 11	ENST00000251412.8	NP_057521.1	Q9NRH3
TUBG2	NM_001320509.2 link	c.913C>T	p.Arg305Trp	missense_variant	Exon 10 of 12		NP_001307438.1	A0A1B4Z394
TUBG2	XM_047435757.1 link	c.427C>T	p.Arg143Trp	missense_variant	Exon 6 of 8		XP_047291713.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBG2	ENST00000251412.8 link	c.886C>T	p.Arg296Trp	missense_variant	Exon 9 of 11	1	NM_016437.3	ENSP00000251412.6		Q9NRH3
TUBG2	ENST00000588870.1 link	n.1284C>T		non_coding_transcript_exon_variant	Exon 7 of 9	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461664

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.0000224

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111842

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 14, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.886C>T (p.R296W) alteration is located in exon 9 (coding exon 9) of the TUBG2 gene. This alteration results from a C to T substitution at nucleotide position 886, causing the arginine (R) at amino acid position 296 to be replaced by a tryptophan (W). 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

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.52

FATHMM_MKL

Uncertain

0.81

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.23

MutationAssessor

Pathogenic

3.5

PhyloP100

0.62

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-7.6

REVEL

Uncertain

0.44

Sift

Uncertain

0.019

Sift4G

Uncertain

0.016

Polyphen

0.99

Vest4

0.73

MutPred

0.60

Gain of catalytic residue at M294 (P = 0.0696);

MVP

0.77

MPC

1.2

ClinPred

1.0

GERP RS

-4.3

Varity_R

0.67

gMVP

0.92

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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17-42666129-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over