10-133279872-C-A

Variant names:

• chr10-133279872-C-A
• rs372338719
• NM_006659.4:c.2603G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006659.4(TUBGCP2):​c.2603G>T​(p.Arg868Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,500 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. R868H) 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.79
• 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):

• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29406747).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBGCP2	NM_006659.4	MANE Select	c.2603G>T	p.Arg868Leu	missense	Exon 18 of 18	NP_006650.1	Q9BSJ2-1
	TUBGCP2	NM_001256617.2		c.2687G>T	p.Arg896Leu	missense	Exon 19 of 19	NP_001243546.1	Q9BSJ2-4
	TUBGCP2	NM_001256618.2		c.2213G>T	p.Arg738Leu	missense	Exon 17 of 17	NP_001243547.1	Q9BSJ2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBGCP2	ENST00000252936.8	TSL:2 MANE Select	c.2603G>T	p.Arg868Leu	missense	Exon 18 of 18	ENSP00000252936.3	Q9BSJ2-1
	TUBGCP2	ENST00000543663.6	TSL:1	c.2687G>T	p.Arg896Leu	missense	Exon 19 of 19	ENSP00000446093.1	Q9BSJ2-4
	TUBGCP2	ENST00000682161.1		c.2672G>T	p.Arg891Leu	missense	Exon 17 of 17	ENSP00000507509.1	A0A804HJH7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456500 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724370

African (AFR) AF: 0.00 AC: 0 AN: 33316

American (AMR) AF: 0.00 AC: 0 AN: 43976

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39460

South Asian (SAS) AF: 0.00 AC: 0 AN: 85542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110178

Other (OTH) AF: 0.00 AC: 0 AN: 60196

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.21
Sift	Benign	0.11	T
Sift4G	Benign	0.18	T
Polyphen		0.80	P
Vest4		0.47
MutPred		0.48		Loss of disorder (P = 0.0452)
MVP		0.52
MPC		1.1
ClinPred		0.95	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.66
Mutation Taster		=12/88	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

dbSNP: rs372338719; hg19: chr10-135093376;