chr22-50227980-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_020461.4(TUBGCP6):c.1339G>A(p.Val447Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000273 in 1,571,164 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V447A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00033 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 1 hom. )

Consequence

TUBGCP6
NM_020461.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 7.91

Publications

3 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.038603842).

BP6

Variant 22-50227980-C-T is Benign according to our data. Variant chr22-50227980-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521245.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000335 (51/152338) while in subpopulation AMR AF = 0.00144 (22/15300). AF 95% confidence interval is 0.000973. There are 1 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020461.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBGCP6	NM_020461.4	MANE Select	c.1339G>A	p.Val447Ile	missense	Exon 5 of 25	NP_065194.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TUBGCP6	ENST00000248846.10	TSL:1 MANE Select	c.1339G>A	p.Val447Ile	missense	Exon 5 of 25	ENSP00000248846.5
TUBGCP6	ENST00000439308.7	TSL:1	n.1339G>A		non_coding_transcript_exon	Exon 5 of 25	ENSP00000397387.2
TUBGCP6	ENST00000498611.5	TSL:1	n.1872G>A		non_coding_transcript_exon	Exon 5 of 23

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000351

AC:

AN:

182282

AF XY:

0.000279

show subpopulations

Gnomad AFR exome

AF:

0.000263

Gnomad AMR exome

AF:

0.00124

Gnomad ASJ exome

AF:

0.000115

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000183

Gnomad NFE exome

AF:

0.000287

Gnomad OTH exome

AF:

0.000617

GnomAD4 exome

AF:

0.000266

AC:

378

AN:

1418826

Hom.:

Cov.:

AF XY:

0.000254

AC XY:

178

AN XY:

701376

show subpopulations

African (AFR)

AF:

0.000303

AC:

AN:

33018

American (AMR)

AF:

0.00106

AC:

AN:

36838

Ashkenazi Jewish (ASJ)

AF:

0.0000396

AC:

AN:

25260

East Asian (EAS)

AF:

0.00

AC:

AN:

38320

South Asian (SAS)

AF:

0.00

AC:

AN:

80574

European-Finnish (FIN)

AF:

0.000119

AC:

AN:

50440

Middle Eastern (MID)

AF:

0.00110

AC:

AN:

5470

European-Non Finnish (NFE)

AF:

0.000258

AC:

281

AN:

1090044

Other (OTH)

AF:

0.000595

AC:

AN:

58862

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000335

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

41582

American (AMR)

AF:

0.00144

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68022

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

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:

0.000152

Hom.:

Bravo

AF:

0.000382

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.000203

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Oct 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 447 of the TUBGCP6 protein (p.Val447Ile). This variant is present in population databases (rs182347943, gnomAD 0.1%). 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: 521245). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

Inborn genetic diseases

Benign:1

Oct 03, 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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.049

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.86

M_CAP

Benign

0.022

MetaRNN

Benign

0.039

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.9

PhyloP100

7.9

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.81

REVEL

Benign

0.25

Sift

Uncertain

0.018

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.38

MVP

0.32

MPC

0.48

ClinPred

0.16

GERP RS

5.4

Varity_R

0.095

gMVP

0.27

Mutation Taster

=82/18

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over