Genetic Variant TUBGCP2:p.Thr881Asn (chr10-133279833-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006659.4(TUBGCP2):c.2642C>A(p.Thr881Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T881I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TUBGCP2
NM_006659.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.475

Publications

1 publications found

Variant links:

Genes affected

TUBGCP2 (HGNC:18599): (tubulin gamma complex component 2) Predicted to enable gamma-tubulin binding activity. Predicted to contribute to microtubule minus-end binding activity. Involved in brain development and neuron migration. Located in centrosome and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TUBGCP2 Gene-Disease associations (from GenCC):

Norman-Roberts syndrome
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

TUBGCP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06204015).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBGCP2	NM_006659.4 link	c.2642C>A	p.Thr881Asn	missense_variant	Exon 18 of 18	ENST00000252936.8	NP_006650.1	Q9BSJ2-1Q53EQ3
TUBGCP2	NM_001256617.2 link	c.2726C>A	p.Thr909Asn	missense_variant	Exon 19 of 19		NP_001243546.1	Q9BSJ2-4
TUBGCP2	NM_001256618.2 link	c.2252C>A	p.Thr751Asn	missense_variant	Exon 17 of 17		NP_001243547.1	Q9BSJ2-3
TUBGCP2	NR_046330.2 link	n.3362C>A		non_coding_transcript_exon_variant	Exon 18 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBGCP2	ENST00000252936.8 link	c.2642C>A	p.Thr881Asn	missense_variant	Exon 18 of 18	2	NM_006659.4	ENSP00000252936.3		Q9BSJ2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000458

AC:

AN:

218118

AF XY:

0.00000840

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1444196

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717398

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32902

American (AMR)

AF:

0.00

AC:

AN:

41800

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25804

East Asian (EAS)

AF:

0.00

AC:

AN:

38626

South Asian (SAS)

AF:

0.0000119

AC:

AN:

83848

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51172

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104630

Other (OTH)

AF:

0.00

AC:

AN:

59676

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000828

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.90

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.058

T;.;.;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.39

.;T;T;T;T

M_CAP

Benign

0.0036

MetaRNN

Benign

0.062

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;.;N;.

PhyloP100

0.47

PrimateAI

Benign

0.47

PROVEAN

Benign

0.30

N;N;N;N;N

REVEL

Benign

0.017

Sift

Uncertain

0.012

D;D;D;D;D

Sift4G

Benign

0.14

T;T;T;T;T

Polyphen

0.0090

B;.;.;B;.

Vest4

0.029

MutPred

0.14

Loss of glycosylation at T881 (P = 0.0112);.;.;Loss of glycosylation at T881 (P = 0.0112);.;

MVP

0.31

MPC

0.32

ClinPred

0.050

GERP RS

-0.37

Varity_R

0.030

gMVP

0.16

Mutation Taster

=98/2

polymorphism

(source)

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

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10-133279833-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over