10-133281345-A-G

Variant names:

• chr10-133281345-A-G
• NM_006659.4:c.2501T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006659.4(TUBGCP2):​c.2501T>C​(p.Leu834Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBGCP2 NM_006659.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.19
• Publications: 0 publications found

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

ACMG classification

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, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBGCP2	NM_006659.4	c.2501T>C	p.Leu834Pro	missense_variant	Exon 17 of 18	ENST00000252936.8	NP_006650.1
TUBGCP2	NM_001256617.2	c.2585T>C	p.Leu862Pro	missense_variant	Exon 18 of 19		NP_001243546.1
TUBGCP2	NM_001256618.2	c.2111T>C	p.Leu704Pro	missense_variant	Exon 16 of 17		NP_001243547.1
TUBGCP2	NR_046330.2	n.3221T>C		non_coding_transcript_exon_variant	Exon 17 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBGCP2	ENST00000252936.8	c.2501T>C	p.Leu834Pro	missense_variant	Exon 17 of 18	2	NM_006659.4	ENSP00000252936.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2501T>C (p.L834P) alteration is located in exon 17 (coding exon 16) of the TUBGCP2 gene. This alteration results from a T to C substitution at nucleotide position 2501, causing the leucine (L) at amino acid position 834 to be replaced by a proline (P). 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	0.93
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;.;T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	.;D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.;.;M;.
PhyloP100		7.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D
REVEL	Uncertain	0.36
Sift	Benign	0.036	D;D;D;D;D
Sift4G	Uncertain	0.042	D;D;D;D;D
Polyphen		0.72	P;.;.;P;.
Vest4		0.91
MutPred		0.75		Loss of stability (P = 0.0242);.;.;Loss of stability (P = 0.0242);.;
MVP		0.70
MPC		1.2
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.80
gMVP		0.86
Mutation Taster		=14/86	disease causing

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

Other links and lift over

hg19: chr10-135094849;