22-50244299-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_020461.4(TUBGCP6):c.161C>G(p.Thr54Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,613,656 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 3 hom. )

Consequence

TUBGCP6
NM_020461.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.12

Publications

4 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00803265).

BP6

Variant 22-50244299-G-C is Benign according to our data. Variant chr22-50244299-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 437163.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000623 (95/152370) while in subpopulation NFE AF = 0.0011 (75/68038). AF 95% confidence interval is 0.000901. There are 0 homozygotes in GnomAd4. There are 46 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TUBGCP6	NM_020461.4 link	c.161C>G	p.Thr54Ser	missense_variant	Exon 1 of 25	ENST00000248846.10	NP_065194.3
TUBGCP6	XR_001755343.3 link	n.725C>G		non_coding_transcript_exon_variant	Exon 1 of 20
TUBGCP6	XR_007067982.1 link	n.725C>G		non_coding_transcript_exon_variant	Exon 1 of 19
TUBGCP6	XR_938347.3 link	n.725C>G		non_coding_transcript_exon_variant	Exon 1 of 23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TUBGCP6	ENST00000248846.10 link	c.161C>G	p.Thr54Ser	missense_variant	Exon 1 of 25	1	NM_020461.4	ENSP00000248846.5
TUBGCP6	ENST00000439308.7 link	n.161C>G		non_coding_transcript_exon_variant	Exon 1 of 25	1		ENSP00000397387.2
TUBGCP6	ENST00000498611.5 link	n.694C>G		non_coding_transcript_exon_variant	Exon 1 of 23	1

Frequencies

GnomAD3 genomes

AF:

0.000624

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00110

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000661

AC:

166

AN:

251224

AF XY:

0.000684

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.00121

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.00127

AC:

1862

AN:

1461286

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

867

AN XY:

726912

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33480

American (AMR)

AF:

0.000335

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000322

AC:

AN:

52832

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00158

AC:

1757

AN:

1112002

Other (OTH)

AF:

0.000960

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

125

250

376

501

626

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<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:

0.000623

AC:

AN:

152370

Hom.:

Cov.:

AF XY:

0.000617

AC XY:

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41582

American (AMR)

AF:

0.000457

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000376

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00110

AC:

AN:

68038

Other (OTH)

AF:

0.000473

AC:

AN:

2116

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:

0.000643

Hom.:

Bravo

AF:

0.000835

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000601

AC:

EpiCase

AF:

0.00196

EpiControl

AF:

0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 18, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Oct 12, 2021

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.

not provided

Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.67

CADD

Benign

5.1

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.011

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.46

T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.0080

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.7

L;.

PhyloP100

2.1

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.47

N;N

REVEL

Benign

0.048

Sift

Benign

0.48

T;T

Sift4G

Benign

0.53

T;T

Vest4

0.15

ClinPred

0.020

GERP RS

-1.2

Varity_R

0.030

gMVP

0.13

Mutation Taster

=99/1

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