22-50220963-A-C

Variant names:

• chr22-50220963-A-C
• rs879175668
• NM_020461.4:c.3396T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_020461.4(TUBGCP6):​c.3396T>G​(p.Asn1132Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N1132N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBGCP6 NM_020461.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.814
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• microcephaly and chorioretinopathy 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1871323).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBGCP6	NM_020461.4	c.3396T>G	p.Asn1132Lys	missense_variant	Exon 16 of 25	ENST00000248846.10	NP_065194.3
TUBGCP6	XR_001755343.3	n.3960T>G		non_coding_transcript_exon_variant	Exon 16 of 20
TUBGCP6	XR_938347.3	n.3960T>G		non_coding_transcript_exon_variant	Exon 16 of 23
TUBGCP6	XR_007067982.1	n.3049-948T>G		intron_variant	Intron 15 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBGCP6	ENST00000248846.10	c.3396T>G	p.Asn1132Lys	missense_variant	Exon 16 of 25	1	NM_020461.4	ENSP00000248846.5
TUBGCP6	ENST00000439308.7	n.3396T>G		non_coding_transcript_exon_variant	Exon 16 of 25	1		ENSP00000397387.2
TUBGCP6	ENST00000498611.5	n.3617+312T>G		intron_variant	Intron 16 of 22	1
TUBGCP6	ENST00000491449.5	n.1703T>G		non_coding_transcript_exon_variant	Exon 8 of 16	5

Frequencies

GnomAD3 genomes AF: 0.0000111 AC: 1 AN: 90392 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000381

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000164 AC: 2 AN: 1222882 Hom.: 0 Cov.: 37 AF XY: 0.00000164 AC XY: 1 AN XY: 608000

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25678

American (AMR) AF: 0.00 AC: 0 AN: 32336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17504

East Asian (EAS) AF: 0.00 AC: 0 AN: 17538

South Asian (SAS) AF: 0.00 AC: 0 AN: 80412

European-Finnish (FIN) AF: 0.0000544 AC: 2 AN: 36760

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4634

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 963034

Other (OTH) AF: 0.00 AC: 0 AN: 44986

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000111 AC: 1 AN: 90488 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 44010

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23436

American (AMR) AF: 0.00 AC: 0 AN: 9024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2330

East Asian (EAS) AF: 0.00 AC: 0 AN: 2492

South Asian (SAS) AF: 0.000383 AC: 1 AN: 2614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4776

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 108

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 43916

Other (OTH) AF: 0.00 AC: 0 AN: 1346

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.9
DANN	Uncertain	0.99
DEOGEN2	Benign	0.040	T;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;.
PhyloP100		-0.81
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.082
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.020	D;D
Polyphen		0.94	P;.
Vest4		0.24
MutPred		0.57		Gain of ubiquitination at N1132 (P = 0.0192);Gain of ubiquitination at N1132 (P = 0.0192);
MVP		0.29
MPC		0.12
ClinPred		0.54	D
GERP RS		0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.073
gMVP		0.66
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs879175668; hg19: chr22-50659392; COSMIC: COSV104560509; COSMIC: COSV104560509;