rs4838865

chr22-50226183-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020461.4(TUBGCP6):c.1700T>C(p.Leu567Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.771 in 1,613,956 control chromosomes in the GnomAD database, including 482,265 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. L567L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.81 (51135 hom., cov: 32)
  • Exomes 𝑓: 0.77 (431130 hom.)
• Consequence: TUBGCP6 NM_020461.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.798

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.319099E-7).
• BP6: Variant 22-50226183-A-G is Benign according to our data. Variant chr22-50226183-A-G is described in ClinVar as [Benign]. Clinvar id is 518329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50226183-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBGCP6	NM_020461.4	c.1700T>C	p.Leu567Ser	missense_variant	9/25	ENST00000248846.10
TUBGCP6	XR_001755343.3	n.2264T>C		non_coding_transcript_exon_variant	9/20
TUBGCP6	XR_007067982.1	n.2264T>C		non_coding_transcript_exon_variant	9/19
TUBGCP6	XR_938347.3	n.2264T>C		non_coding_transcript_exon_variant	9/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBGCP6	ENST00000248846.10	c.1700T>C	p.Leu567Ser	missense_variant	9/25	1	NM_020461.4	P1

Frequencies

GnomAD3 genomes AF: 0.814 AC: 123790 AN: 152028 Hom.: 51086 Cov.: 32

Gnomad AFR AF: 0.952

Gnomad AMI AF: 0.686

Gnomad AMR AF: 0.720

Gnomad ASJ AF: 0.713

Gnomad EAS AF: 0.826

Gnomad SAS AF: 0.894

Gnomad FIN AF: 0.796

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.756

Gnomad OTH AF: 0.791

GnomAD3 exomes AF: 0.782 AC: 196476 AN: 251388 Hom.: 77655 AF XY: 0.788 AC XY: 107016 AN XY: 135862

Gnomad AFR exome AF: 0.959

Gnomad AMR exome AF: 0.654

Gnomad ASJ exome AF: 0.719

Gnomad EAS exome AF: 0.830

Gnomad SAS exome AF: 0.890

Gnomad FIN exome AF: 0.795

Gnomad NFE exome AF: 0.762

Gnomad OTH exome AF: 0.770

GnomAD4 exome AF: 0.766 AC: 1120144 AN: 1461810 Hom.: 431130 Cov.: 76 AF XY: 0.769 AC XY: 559426 AN XY: 727198

Gnomad4 AFR exome AF: 0.959

Gnomad4 AMR exome AF: 0.662

Gnomad4 ASJ exome AF: 0.716

Gnomad4 EAS exome AF: 0.828

Gnomad4 SAS exome AF: 0.887

Gnomad4 FIN exome AF: 0.797

Gnomad4 NFE exome AF: 0.752

Gnomad4 OTH exome AF: 0.779

GnomAD4 genome AF: 0.814 AC: 123888 AN: 152146 Hom.: 51135 Cov.: 32 AF XY: 0.817 AC XY: 60786 AN XY: 74364

Gnomad4 AFR AF: 0.952

Gnomad4 AMR AF: 0.719

Gnomad4 ASJ AF: 0.713

Gnomad4 EAS AF: 0.826

Gnomad4 SAS AF: 0.895

Gnomad4 FIN AF: 0.796

Gnomad4 NFE AF: 0.756

Gnomad4 OTH AF: 0.786

Alfa AF: 0.768 Hom.: 108928

Bravo AF: 0.811

TwinsUK AF: 0.746 AC: 2766

ALSPAC AF: 0.743 AC: 2865

ESP6500AA AF: 0.949 AC: 4183

ESP6500EA AF: 0.760 AC: 6539

ExAC AF: 0.791 AC: 96041

Asia WGS AF: 0.847 AC: 2945 AN: 3478

EpiCase AF: 0.761

EpiControl AF: 0.756

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly and chorioretinopathy 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2018	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.84
Dann	Benign	0.32
DEOGEN2	Benign	0.018	T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.023	T;T
MetaRNN	Benign	6.3e-7	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.51	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.1	N;N
REVEL	Benign	0.040
Sift	Benign	0.69	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.0050	B;.
Vest4		0.063
MPC		0.15
ClinPred		0.0014	T
GERP RS		-5.7
Varity_R		0.013
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4838865; hg19: chr22-50664612;