rs142435821

Positions:

• chr22-50229501-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_020461.4(TUBGCP6):​c.1193C>T​(p.Ser398Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000733 in 1,610,964 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. S398S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00060 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (0 hom.)
• Consequence: TUBGCP6 NM_020461.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 4.42

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1704874).
• BP6: Variant 22-50229501-G-A is Benign according to our data. Variant chr22-50229501-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 437160.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBGCP6	NM_020461.4	c.1193C>T	p.Ser398Leu	missense_variant	4/25	ENST00000248846.10
TUBGCP6	XR_001755343.3	n.1757C>T		non_coding_transcript_exon_variant	4/20
TUBGCP6	XR_007067982.1	n.1757C>T		non_coding_transcript_exon_variant	4/19
TUBGCP6	XR_938347.3	n.1757C>T		non_coding_transcript_exon_variant	4/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBGCP6	ENST00000248846.10	c.1193C>T	p.Ser398Leu	missense_variant	4/25	1	NM_020461.4	P1
TUBGCP6	ENST00000439308.6	c.1193C>T	p.Ser398Leu	missense_variant	4/25	1
TUBGCP6	ENST00000498611.5	n.1726C>T		non_coding_transcript_exon_variant	4/23	1
TUBGCP6	ENST00000434349.1	c.425C>T	p.Ser142Leu	missense_variant	3/6	5

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152200 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000551 AC: 134 AN: 243190 Hom.: 0 AF XY: 0.000530 AC XY: 70 AN XY: 132138

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.000914

Gnomad ASJ exome AF: 0.000203

Gnomad EAS exome AF: 0.0000555

Gnomad SAS exome AF: 0.000101

Gnomad FIN exome AF: 0.0000955

Gnomad NFE exome AF: 0.000787

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.000747 AC: 1090 AN: 1458646 Hom.: 0 Cov.: 31 AF XY: 0.000704 AC XY: 511 AN XY: 725422

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.000722

Gnomad4 ASJ exome AF: 0.0000767

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000700

Gnomad4 FIN exome AF: 0.000304

Gnomad4 NFE exome AF: 0.000888

Gnomad4 OTH exome AF: 0.000680

GnomAD4 genome AF: 0.000597 AC: 91 AN: 152318 Hom.: 1 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74480

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000742 Hom.: 0

Bravo AF: 0.000582

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000511 AC: 62

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

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 398 of the TUBGCP6 protein (p.Ser398Leu). This variant is present in population databases (rs142435821, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. 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: 437160). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TUBGCP6: BP4 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 23, 2016

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2022

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	0.10
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Benign	0.19
Sift	Benign	0.076	T;D
Sift4G	Uncertain	0.038	D;D
Polyphen		1.0	D;.
Vest4		0.55
MVP		0.41
MPC		0.45
ClinPred		0.091	T
GERP RS		5.0
Varity_R		0.14
gMVP		0.40

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: rs142435821; hg19: chr22-50667930;