Genetic Variant NM_006659.4:c.2701G>T (chr10-133279774-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.2701G>T(p.Ala901Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000356 in 1,405,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A901T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

TUBGCP2
NM_006659.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.72

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):

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:

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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=0.17369926).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBGCP2	NM_006659.4 link	c.2701G>T	p.Ala901Ser	missense_variant	Exon 18 of 18	ENST00000252936.8	NP_006650.1	Q9BSJ2-1Q53EQ3
TUBGCP2	NM_001256617.2 link	c.2785G>T	p.Ala929Ser	missense_variant	Exon 19 of 19		NP_001243546.1	Q9BSJ2-4
TUBGCP2	NM_001256618.2 link	c.2311G>T	p.Ala771Ser	missense_variant	Exon 17 of 17		NP_001243547.1	Q9BSJ2-3
TUBGCP2	NR_046330.2 link	n.3421G>T		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.2701G>T	p.Ala901Ser	missense_variant	Exon 18 of 18	2	NM_006659.4	ENSP00000252936.3		Q9BSJ2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000356

AC:

AN:

1405696

Hom.:

Cov.:

AF XY:

0.00000288

AC XY:

AN XY:

694408

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31872

American (AMR)

AF:

0.00

AC:

AN:

36506

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25222

East Asian (EAS)

AF:

0.00

AC:

AN:

36214

South Asian (SAS)

AF:

0.00

AC:

AN:

80072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48746

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00000462

AC:

AN:

1083116

Other (OTH)

AF:

0.00

AC:

AN:

58258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.072

T;.;.;T;T

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.76

.;T;T;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.17

T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.5

L;.;.;L;.

PhyloP100

1.7

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.35

N;N;N;N;N

REVEL

Benign

0.12

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Benign

0.48

T;T;T;T;T

Polyphen

0.80

P;.;.;P;.

Vest4

0.11

MutPred

0.16

Gain of glycosylation at A901 (P = 0.0162);.;.;Gain of glycosylation at A901 (P = 0.0162);.;

MVP

0.36

MPC

0.26

ClinPred

0.67

GERP RS

4.8

Varity_R

0.078

gMVP

0.27

Mutation Taster

=87/13

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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NM_006659.4:c.2701G>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