chr22-50221071-A-C

Position:

chr22-50221071-A-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_020461.4(TUBGCP6):c.3288T>G(p.Asp1096Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000661 in 1,528,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

TUBGCP6
NM_020461.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -7.18

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.007681191).

BP6

Variant 22-50221071-A-C is Benign according to our data. Variant chr22-50221071-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 966787.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}. Variant chr22-50221071-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000456 (52/114106) while in subpopulation AFR AF= 0.00168 (49/29182). AF 95% confidence interval is 0.0013. There are 0 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TUBGCP6	NM_020461.4 linkuse as main transcript	c.3288T>G	p.Asp1096Glu	missense_variant	16/25	ENST00000248846.10	NP_065194.3
TUBGCP6	XR_001755343.3 linkuse as main transcript	n.3852T>G		non_coding_transcript_exon_variant	16/20
TUBGCP6	XR_938347.3 linkuse as main transcript	n.3852T>G		non_coding_transcript_exon_variant	16/23
TUBGCP6	XR_007067982.1 linkuse as main transcript	n.3048+957T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBGCP6	ENST00000248846.10 linkuse as main transcript	c.3288T>G	p.Asp1096Glu	missense_variant	16/25	1	NM_020461.4	ENSP00000248846	P1	Q96RT7-1
TUBGCP6	ENST00000439308.6 linkuse as main transcript	c.3288T>G	p.Asp1096Glu	missense_variant	16/25	1		ENSP00000397387
TUBGCP6	ENST00000498611.5 linkuse as main transcript	n.3617+204T>G		intron_variant, non_coding_transcript_variant		1
TUBGCP6	ENST00000491449.5 linkuse as main transcript	n.1595T>G		non_coding_transcript_exon_variant	8/16	5

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

114020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00165

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000639

GnomAD3 exomes

AF:

0.0000717

AC:

AN:

251208

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.0000872

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000346

AC:

AN:

1414204

Hom.:

Cov.:

AF XY:

0.0000298

AC XY:

AN XY:

704372

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.000117

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.26e-7

Gnomad4 OTH exome

AF:

0.000141

GnomAD4 genome

AF:

0.000456

AC:

AN:

114106

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

55318

show subpopulations

Gnomad4 AFR

AF:

0.00168

Gnomad4 AMR

AF:

0.000176

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000631

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.000366

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Microcephaly and chorioretinopathy 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 11, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 07, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1096 of the TUBGCP6 protein (p.Asp1096Glu). This variant is present in population databases (rs6010209, 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: 966787). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2023

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

0.18

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.0050

DANN

Benign

0.57

DEOGEN2

Benign

0.016

T;.

Eigen

Benign

-2.5

Eigen_PC

Benign

-2.6

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.44

T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.0077

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.77

N;.

MutationTaster

Benign

0.99

N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

0.0

N;N

REVEL

Benign

0.027

Sift

Benign

0.32

T;T

Sift4G

Benign

0.72

T;T

Polyphen

0.44

B;.

Vest4

0.10

MutPred

0.33

Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);

MVP

0.20

MPC

0.14

ClinPred

0.032

GERP RS

-8.8

Varity_R

0.023

gMVP

0.13

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