10-133279803-G-A

Variant names:

• chr10-133279803-G-A
• rs763452490
• NM_006659.4:c.2672C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_006659.4(TUBGCP2):​c.2672C>T​(p.Pro891Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,572,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: TUBGCP2 NM_006659.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.96
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.067328036).
• BP6: Variant 10-133279803-G-A is Benign according to our data. Variant chr10-133279803-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3065197.

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.2672C>T	p.Pro891Leu	missense	Exon 18 of 18	NP_006650.1	Q9BSJ2-1
	TUBGCP2	NM_001256617.2		c.2756C>T	p.Pro919Leu	missense	Exon 19 of 19	NP_001243546.1	Q9BSJ2-4
	TUBGCP2	NM_001256618.2		c.2282C>T	p.Pro761Leu	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.2672C>T	p.Pro891Leu	missense	Exon 18 of 18	ENSP00000252936.3	Q9BSJ2-1
	TUBGCP2	ENST00000543663.6	TSL:1	c.2756C>T	p.Pro919Leu	missense	Exon 19 of 19	ENSP00000446093.1	Q9BSJ2-4
	TUBGCP2	ENST00000682161.1		c.2741C>T	p.Pro914Leu	missense	Exon 17 of 17	ENSP00000507509.1	A0A804HJH7

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000382 AC: 7 AN: 183222 AF XY: 0.0000401

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000454

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000268 AC: 38 AN: 1420492 Hom.: 0 Cov.: 31 AF XY: 0.0000256 AC XY: 18 AN XY: 703468

African (AFR) AF: 0.00 AC: 0 AN: 32256

American (AMR) AF: 0.00 AC: 0 AN: 38236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25406

East Asian (EAS) AF: 0.000459 AC: 17 AN: 37028

South Asian (SAS) AF: 0.0000368 AC: 3 AN: 81444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49672

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5700

European-Non Finnish (NFE) AF: 0.0000119 AC: 13 AN: 1091928

Other (OTH) AF: 0.0000680 AC: 4 AN: 58822

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74378

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000334 AC: 4

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	-	1	Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.016
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.043	D
Polyphen		0.0010	B
Vest4		0.16
MVP		0.42
MPC		0.29
ClinPred		0.12	T
GERP RS		3.9
Varity_R		0.037
gMVP		0.27
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs763452490; hg19: chr10-135093307;