22-50224426-T-C

Variant names:

• chr22-50224426-T-C
• rs368765755
• NM_020461.4:c.2066-6A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_020461.4(TUBGCP6):​c.2066-6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: TUBGCP6 NM_020461.4 splice_region, intron
• Scores: Splicing: ADA: 0.9313
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2
• Conservation: PhyloP100: -0.294

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_ADA.
• PP5: Variant 22-50224426-T-C is Pathogenic according to our data. Variant chr22-50224426-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 437169.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2, Pathogenic=3}. Variant chr22-50224426-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBGCP6	NM_020461.4	c.2066-6A>G		splice_region_variant, intron_variant	Intron 11 of 24	ENST00000248846.10	NP_065194.3
TUBGCP6	XR_001755343.3	n.2630-6A>G		splice_region_variant, intron_variant	Intron 11 of 19
TUBGCP6	XR_007067982.1	n.2630-6A>G		splice_region_variant, intron_variant	Intron 11 of 18
TUBGCP6	XR_938347.3	n.2630-6A>G		splice_region_variant, intron_variant	Intron 11 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBGCP6	ENST00000248846.10	c.2066-6A>G		splice_region_variant, intron_variant	Intron 11 of 24	1	NM_020461.4	ENSP00000248846.5

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000588

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.0000676 AC: 17 AN: 251494 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135920

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000609 AC: 89 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 38 AN XY: 727236

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000585

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74338

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.000151

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3

Oct 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed with a second TUBGCP6 variant, phase unknown, in two siblings with familial exudative vitreoretinopathy and microcephaly in published literature (PMID: 31077665); Published functional studies demonstrate a damaging effect secondary to a truncated protein (PMID: 31077665); Not observed at significant frequency in large population cohorts (gnomAD); Located in a region that tolerates variation and lacks pathogenic variants; This variant is associated with the following publications: (PMID: 36307859, 37229200, 33458610, 37031378, 31077665) -

Nov 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 11 of the TUBGCP6 gene. It does not directly change the encoded amino acid sequence of the TUBGCP6 protein. This variant is present in population databases (rs368765755, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of microcephaly and chorioretinopathy (PMID: 31077665, 36307859, 37031378). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 437169). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Microcephaly and chorioretinopathy 1 Pathogenic:1 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 07, 2023

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TUBGCP c.2066-6A>G variant occurs in a splice region. This variant has been reported in individuals with clinical features consistent with microcephaly and chorioretinopathy, including in one individual in whom it was confirmed in trans with a likely pathogenic variant in the gene. The c.2066-6A>G variant was shown to segregate with disease in one family in two siblings (PMID: 31077665; 37031378). The highest frequency of this variant in the Genome Aggregation Database is 0.000241 in the African/African American population (version 3.1.2). Functional studies demonstrated that the c.2066-6A>G variant results in the insertion of five intronic nucleotides, which is predicted to lead to a frameshift in the protein reading frame and premature termination of the protein (PMID: 31077665). The c.2066-6A>G variant was identified in trans with a likely pathogenic variant. Based on the available evidence, the c.2066-6A>G variant is classified as likely pathogenic for microcephaly and chorioretinopathy. -

not specified Uncertain:1

Nov 23, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	19
DANN	Benign	0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs368765755; hg19: chr22-50662855;