rs201721812

chr22-50218001-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_020461.4(TUBGCP6):c.5285C>T(p.Pro1762Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 1,611,854 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1762P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (3 hom.)
• Consequence: TUBGCP6 NM_020461.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.26

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003908932).
• BP6: Variant 22-50218001-G-A is Benign according to our data. Variant chr22-50218001-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212516.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000243 (37/152220) while in subpopulation EAS AF= 0.00543 (28/5152). AF 95% confidence interval is 0.00386. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBGCP6	NM_020461.4	c.5285C>T	p.Pro1762Leu	missense_variant	24/25	ENST00000248846.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBGCP6	ENST00000248846.10	c.5285C>T	p.Pro1762Leu	missense_variant	24/25	1	NM_020461.4	P1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152102 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00542

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000562 AC: 138 AN: 245762 Hom.: 0 AF XY: 0.000544 AC XY: 73 AN XY: 134082

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00615

Gnomad SAS exome AF: 0.0000656

Gnomad FIN exome AF: 0.000234

Gnomad NFE exome AF: 0.000163

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000210 AC: 306 AN: 1459634 Hom.: 3 Cov.: 36 AF XY: 0.000172 AC XY: 125 AN XY: 726214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00398

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.000114

Gnomad4 NFE exome AF: 0.0000666

Gnomad4 OTH exome AF: 0.000929

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.000296 AC XY: 22 AN XY: 74434

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00543

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000393

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000505 AC: 61

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2018	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 19, 2015

- -

Microcephaly and chorioretinopathy 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Sep 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-0.087
Eigen_PC	Benign	-0.069
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0039	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	0.95	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Benign	0.11
Sift	Benign	0.053	T;D
Sift4G	Benign	0.078	T;T
Polyphen		0.99	D;.
Vest4		0.54
MVP		0.46
MPC		0.39
ClinPred		0.13	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.085
gMVP		0.41

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

Other links and lift over

dbSNP: rs201721812; hg19: chr22-50656430;