Genetic Variant TUBGCP6:p.Arg1128Arg (chr22-50220977-T-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7

The NM_020461.4(TUBGCP6):c.3382A>C(p.Arg1128Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. 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 0.0027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TUBGCP6
NM_020461.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.0710

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 22-50220977-T-G is Benign according to our data. Variant chr22-50220977-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 437149.

BP7

Synonymous conserved (PhyloP=-0.071 with no splicing effect.

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.3382A>C	p.Arg1128Arg	synonymous	Exon 16 of 25	NP_065194.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TUBGCP6	ENST00000248846.10	TSL:1 MANE Select	c.3382A>C	p.Arg1128Arg	synonymous	Exon 16 of 25	ENSP00000248846.5
TUBGCP6	ENST00000439308.7	TSL:1	n.3382A>C		non_coding_transcript_exon	Exon 16 of 25	ENSP00000397387.2
TUBGCP6	ENST00000498611.5	TSL:1	n.3617+298A>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00264

AC:

272

AN:

103018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00354

Gnomad AMI

AF:

0.00890

Gnomad AMR

AF:

0.00320

Gnomad ASJ

AF:

0.00235

Gnomad EAS

AF:

0.00241

Gnomad SAS

AF:

0.00129

Gnomad FIN

AF:

0.00183

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00215

Gnomad OTH

AF:

0.00418

GnomAD2 exomes

AF:

0.00000427

AC:

AN:

234168

AF XY:

0.00000785

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000616

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000111

AC:

AN:

1435400

Hom.:

Cov.:

AF XY:

0.00000700

AC XY:

AN XY:

714454

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32516

American (AMR)

AF:

0.000120

AC:

AN:

41666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24892

East Asian (EAS)

AF:

0.000130

AC:

AN:

38334

South Asian (SAS)

AF:

0.0000354

AC:

AN:

84732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52910

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5662

European-Non Finnish (NFE)

AF:

0.00000274

AC:

AN:

1096104

Other (OTH)

AF:

0.00

AC:

AN:

58584

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.244

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00267

AC:

275

AN:

103084

Hom.:

Cov.:

AF XY:

0.00227

AC XY:

115

AN XY:

50688

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00357

AC:

AN:

26356

American (AMR)

AF:

0.00330

AC:

AN:

10316

Ashkenazi Jewish (ASJ)

AF:

0.00235

AC:

AN:

2554

East Asian (EAS)

AF:

0.00272

AC:

AN:

3304

South Asian (SAS)

AF:

0.00129

AC:

AN:

3098

European-Finnish (FIN)

AF:

0.00183

AC:

AN:

6544

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00215

AC:

105

AN:

48808

Other (OTH)

AF:

0.00415

AC:

AN:

1446

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.258

Heterozygous variant carriers

101

134

168

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:

0.0386

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TUBGCP6: BP4, BP7

not specified

Uncertain:1

Feb 07, 2017

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.7

(source)

DANN

Benign

0.42

PhyloP100

-0.071

Mutation Taster

=100/0

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