rs142435821

Positions:

chr22-50229501-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

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).

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

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 links:

TUBGCP6 (HGNC:):

TUBGCP6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 id is 437160.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBGCP6	NM_020461.4 linkuse as main transcript	c.1193C>T	p.Ser398Leu	missense_variant	4/25	ENST00000248846.10	NP_065194.3	Q96RT7-1
TUBGCP6	XR_001755343.3 linkuse as main transcript	n.1757C>T		non_coding_transcript_exon_variant	4/20
TUBGCP6	XR_007067982.1 linkuse as main transcript	n.1757C>T		non_coding_transcript_exon_variant	4/19
TUBGCP6	XR_938347.3 linkuse as main transcript	n.1757C>T		non_coding_transcript_exon_variant	4/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TUBGCP6	ENST00000248846.10 linkuse as main transcript	c.1193C>T	p.Ser398Leu	missense_variant	4/25	1	NM_020461.4	ENSP00000248846.5	Q96RT7-1
TUBGCP6	ENST00000439308.6 linkuse as main transcript	c.1193C>T	p.Ser398Leu	missense_variant	4/25	1		ENSP00000397387.2	E7EQL8
TUBGCP6	ENST00000498611.5 linkuse as main transcript	n.1726C>T		non_coding_transcript_exon_variant	4/23	1
TUBGCP6	ENST00000434349.1 linkuse as main transcript	c.422C>T	p.Ser141Leu	missense_variant	3/6	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

GnomAD3 exomes

AF:

0.000551

AC:

134

AN:

243190

Hom.:

AF XY:

0.000530

AC XY:

AN XY:

132138

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 SAS exome

AF:

0.000101

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

Gnomad4 AFR exome

AF:

0.0000898

Gnomad4 AMR exome

AF:

0.000722

Gnomad4 ASJ exome

AF:

0.0000767

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000700

Gnomad4 FIN exome

AF:

0.000304

Gnomad4 NFE exome

AF:

0.000888

Gnomad4 OTH exome

AF:

0.000680

GnomAD4 genome

AF:

0.000597

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00101

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000742

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TUBGCP6: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	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. -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 23, 2016

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2022

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

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;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over