NM_020461.4:c.1193C>T

Variant names:

• chr22-50229501-G-A
• rs142435821
• NM_020461.4:c.1193C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

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:3 B:2
• Conservation: PhyloP100: 4.42
• Publications: 2 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: Benign. The variant received -7 ACMG points.

• 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 VariationId is 437160.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000597 (91/152318) while in subpopulation NFE AF = 0.00101 (69/68032). AF 95% confidence interval is 0.000821. There are 1 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020461.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBGCP6	NM_020461.4	MANE Select	c.1193C>T	p.Ser398Leu	missense	Exon 4 of 25	NP_065194.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBGCP6	ENST00000248846.10	TSL:1 MANE Select	c.1193C>T	p.Ser398Leu	missense	Exon 4 of 25	ENSP00000248846.5
	TUBGCP6	ENST00000439308.7	TSL:1	n.1193C>T		non_coding_transcript_exon	Exon 4 of 25	ENSP00000397387.2
	TUBGCP6	ENST00000498611.5	TSL:1	n.1726C>T		non_coding_transcript_exon	Exon 4 of 23

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

GnomAD2 exomes AF: 0.000551 AC: 134 AN: 243190 AF XY: 0.000530

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 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

African (AFR) AF: 0.0000898 AC: 3 AN: 33422

American (AMR) AF: 0.000722 AC: 32 AN: 44348

Ashkenazi Jewish (ASJ) AF: 0.0000767 AC: 2 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39594

South Asian (SAS) AF: 0.0000700 AC: 6 AN: 85712

European-Finnish (FIN) AF: 0.000304 AC: 16 AN: 52612

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5762

European-Non Finnish (NFE) AF: 0.000888 AC: 986 AN: 1110850

Other (OTH) AF: 0.000680 AC: 41 AN: 60276

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

African (AFR) AF: 0.0000962 AC: 4 AN: 41566

American (AMR) AF: 0.000849 AC: 13 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000650 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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.4
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.19
Sift	Benign	0.076	T
Sift4G	Uncertain	0.038	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
Mutation Taster		=75/25	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: rs142435821; hg19: chr22-50667930; COSMIC: COSV108017984; COSMIC: COSV108017984;