17-82752198-C-T

Variant names:

• chr17-82752198-C-T
• rs1370974061
• NM_005993.5:c.5C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005993.5(TBCD):​c.5C>T​(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,369,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: TBCD NM_005993.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0730
• Publications: 0 publications found

Genes affected

TBCD (HGNC:11581): (tubulin folding cofactor D) Cofactor D is one of four proteins (cofactors A, D, E, and C) involved in the pathway leading to correctly folded beta-tubulin from folding intermediates. Cofactors A and D are believed to play a role in capturing and stabilizing beta-tubulin intermediates in a quasi-native confirmation. Cofactor E binds to the cofactor D/beta-tubulin complex; interaction with cofactor C then causes the release of beta-tubulin polypeptides that are committed to the native state. [provided by RefSeq, Jul 2008]

TBCD Gene-Disease associations (from GenCC):

• early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29094535).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005993.5. 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
	TBCD	NM_005993.5	MANE Select	c.5C>T	p.Ala2Val	missense	Exon 1 of 39	NP_005984.3
	TBCD	NM_001411101.1		c.5C>T	p.Ala2Val	missense	Exon 1 of 38	NP_001398030.1	A0A804HLI2
	TBCD	NM_001411102.1		c.5C>T	p.Ala2Val	missense	Exon 1 of 38	NP_001398031.1	A0A804HJ32

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBCD	ENST00000355528.9	TSL:1 MANE Select	c.5C>T	p.Ala2Val	missense	Exon 1 of 39	ENSP00000347719.4	Q9BTW9-1
	TBCD	ENST00000684760.1		c.5C>T	p.Ala2Val	missense	Exon 1 of 40	ENSP00000507696.1	A0A804HJY5
	TBCD	ENST00000684349.1		c.5C>T	p.Ala2Val	missense	Exon 1 of 39	ENSP00000508067.1	A0A804HKT8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000265 AC: 3 AN: 113116 AF XY: 0.0000320

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000926

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000251

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1369242 Hom.: 0 Cov.: 30 AF XY: 0.00000296 AC XY: 2 AN XY: 675426

African (AFR) AF: 0.00 AC: 0 AN: 28060

American (AMR) AF: 0.0000601 AC: 2 AN: 33262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24184

East Asian (EAS) AF: 0.00 AC: 0 AN: 31876

South Asian (SAS) AF: 0.00 AC: 0 AN: 76990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4614

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1068822

Other (OTH) AF: 0.00 AC: 0 AN: 56780

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.86	L
PhyloP100		0.073
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.083
Sift	Benign	0.43	T
Sift4G	Benign	0.74	T
Polyphen		0.0010	B
Vest4		0.098
MutPred		0.23		Loss of glycosylation at S4 (P = 0.208)
MVP		0.22
MPC		0.58
ClinPred		0.076	T
GERP RS		-2.8
PromoterAI		-0.16	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.060
gMVP		0.38

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: rs1370974061; hg19: chr17-80710074; COSMIC: COSV56181373; COSMIC: COSV56181373;