rs142435821

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_020461.4(TUBGCP6):c.1193C>T(p.Ser398Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000733 in 1,610,964 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S398S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00060 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 0 hom. )

Consequence

TUBGCP6
NM_020461.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 4.42

Publications

2 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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1704874).

BP6

Variant 22-50229501-G-A is Benign according to our data. Variant chr22-50229501-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 437160.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000597 (91/152318) while in subpopulation NFE AF = 0.00101 (69/68032). AF 95% confidence interval is 0.000821. There are 1 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBGCP6	NM_020461.4 link	c.1193C>T	p.Ser398Leu	missense_variant	Exon 4 of 25	ENST00000248846.10	NP_065194.3	Q96RT7-1
TUBGCP6	XR_001755343.3 link	n.1757C>T		non_coding_transcript_exon_variant	Exon 4 of 20
TUBGCP6	XR_007067982.1 link	n.1757C>T		non_coding_transcript_exon_variant	Exon 4 of 19
TUBGCP6	XR_938347.3 link	n.1757C>T		non_coding_transcript_exon_variant	Exon 4 of 23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TUBGCP6	ENST00000248846.10 link	c.1193C>T	p.Ser398Leu	missense_variant	Exon 4 of 25	1	NM_020461.4	ENSP00000248846.5	Q96RT7-1
TUBGCP6	ENST00000439308.7 link	n.1193C>T		non_coding_transcript_exon_variant	Exon 4 of 25	1		ENSP00000397387.2	E7EQL8
TUBGCP6	ENST00000498611.5 link	n.1726C>T		non_coding_transcript_exon_variant	Exon 4 of 23	1
TUBGCP6	ENST00000434349.1 link	c.422C>T	p.Ser141Leu	missense_variant	Exon 3 of 6	5		ENSP00000409650.1	H7C358

Frequencies

GnomAD3 genomes

AF:

0.000598

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000551

AC:

134

AN:

243190

AF XY:

0.000530

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.000914

Gnomad ASJ exome

AF:

0.000203

Gnomad EAS exome

AF:

0.0000555

Gnomad FIN exome

AF:

0.0000955

Gnomad NFE exome

AF:

0.000787

Gnomad OTH exome

AF:

0.00118

GnomAD4 exome

AF:

0.000747

AC:

1090

AN:

1458646

Hom.:

Cov.:

AF XY:

0.000704

AC XY:

511

AN XY:

725422

show subpopulations

African (AFR)

AF:

0.0000898

AC:

AN:

33422

American (AMR)

AF:

0.000722

AC:

AN:

44348

Ashkenazi Jewish (ASJ)

AF:

0.0000767

AC:

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39594

South Asian (SAS)

AF:

0.0000700

AC:

AN:

85712

European-Finnish (FIN)

AF:

0.000304

AC:

AN:

52612

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000888

AC:

986

AN:

1110850

Other (OTH)

AF:

0.000680

AC:

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

124

187

249

311

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<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

AF:

0.000597

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41566

American (AMR)

AF:

0.000849

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2114

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

Genome 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

Alfa

AF:

0.000650

Hom.:

Bravo

AF:

0.000582

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000511

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TUBGCP6: BP4 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 398 of the TUBGCP6 protein (p.Ser398Leu). This variant is present in population databases (rs142435821, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TUBGCP6-related conditions. ClinVar contains an entry for this variant (Variation ID: 437160). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Jun 23, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Sep 20, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.0088

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.7

M;.

PhyloP100

4.4

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-4.2

D;D

REVEL

Benign

0.19

Sift

Benign

0.076

T;D

Sift4G

Uncertain

0.038

D;D

Polyphen

1.0

D;.

Vest4

0.55

MVP

0.41

MPC

0.45

ClinPred

0.091

GERP RS

5.0

Varity_R

0.14

gMVP

0.40

Mutation Taster

=75/25

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over