Genetic Variant TUBGCP2:p.Arg871Leu (chr10-133279863-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006659.4(TUBGCP2):c.2612G>T(p.Arg871Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R871H) 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: 1.49

Publications

0 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):

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18786716).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006659.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TUBGCP2	NM_006659.4	MANE Select	c.2612G>T	p.Arg871Leu	missense	Exon 18 of 18	NP_006650.1	Q9BSJ2-1
TUBGCP2	NM_001256617.2		c.2696G>T	p.Arg899Leu	missense	Exon 19 of 19	NP_001243546.1	Q9BSJ2-4
TUBGCP2	NM_001256618.2		c.2222G>T	p.Arg741Leu	missense	Exon 17 of 17	NP_001243547.1	Q9BSJ2-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TUBGCP2	ENST00000252936.8	TSL:2 MANE Select	c.2612G>T	p.Arg871Leu	missense	Exon 18 of 18	ENSP00000252936.3	Q9BSJ2-1
TUBGCP2	ENST00000543663.6	TSL:1	c.2696G>T	p.Arg899Leu	missense	Exon 19 of 19	ENSP00000446093.1	Q9BSJ2-4
TUBGCP2	ENST00000682161.1		c.2681G>T	p.Arg894Leu	missense	Exon 17 of 17	ENSP00000507509.1	A0A804HJH7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1454752

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723422

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:

33248

American (AMR)

AF:

0.00

AC:

AN:

43626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25992

East Asian (EAS)

AF:

0.00

AC:

AN:

39360

South Asian (SAS)

AF:

0.00

AC:

AN:

85260

European-Finnish (FIN)

AF:

0.0000193

AC:

AN:

51940

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109446

Other (OTH)

AF:

0.00

AC:

AN:

60132

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Benign

0.094

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.011

MetaRNN

Benign

0.19

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

PhyloP100

1.5

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.094

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.026

Polyphen

0.17

Vest4

0.25

MutPred

0.42

Loss of disorder (P = 0.0409)

MVP

0.49

MPC

0.55

ClinPred

0.79

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.42

Mutation Taster

=75/25

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over