Genetic Variant TUBGCP6:p.Glu632Lys (chr22-50225883-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020461.4(TUBGCP6):c.1894G>A(p.Glu632Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E632Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TUBGCP6
NM_020461.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.56

Publications

1 publications found

Variant links:

Genes affected

TUBGCP6 (HGNC:18127): (tubulin gamma complex component 6) The protein encoded by this gene is part of a large multisubunit complex required for microtubule nucleation at the centrosome. [provided by RefSeq, Jul 2008]

TUBGCP6 Gene-Disease associations (from GenCC):

microcephaly and chorioretinopathy 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen

TUBGCP6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBGCP6	NM_020461.4 link	c.1894G>A	p.Glu632Lys	missense_variant	Exon 10 of 25	ENST00000248846.10	NP_065194.3	Q96RT7-1
TUBGCP6	XR_001755343.3 link	n.2458G>A		non_coding_transcript_exon_variant	Exon 10 of 20
TUBGCP6	XR_007067982.1 link	n.2458G>A		non_coding_transcript_exon_variant	Exon 10 of 19
TUBGCP6	XR_938347.3 link	n.2458G>A		non_coding_transcript_exon_variant	Exon 10 of 23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBGCP6	ENST00000248846.10 link	c.1894G>A	p.Glu632Lys	missense_variant	Exon 10 of 25	1	NM_020461.4	ENSP00000248846.5		Q96RT7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251166

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461784

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Uncertain

0.031

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.070

T;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.74

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

7.6

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.9

D;D

REVEL

Benign

0.26

Sift

Benign

0.18

T;T

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.98

D;.

Vest4

0.68

MutPred

0.58

Gain of ubiquitination at E632 (P = 0.0258);Gain of ubiquitination at E632 (P = 0.0258);

MVP

0.48

MPC

0.56

ClinPred

0.95

GERP RS

5.2

Varity_R

0.20

gMVP

0.71

Mutation Taster

=57/43

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.39

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.39

Position offset: -3

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over