rs2292971

Variant names:

• chr17-82905981-T-C
• rs2292971
• NM_005993.5:c.1850T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-82905981-T-C
• chr17-82905981-T-G
• chr17-82905981-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005993.5(TBCD):​c.1850T>C​(p.Met617Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 1,607,640 control chromosomes in the GnomAD database, including 157,642 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M617R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.48 (18827 hom., cov: 34)
  • Exomes 𝑓: 0.43 (138815 hom.)
• Consequence: TBCD NM_005993.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.106
• Publications: 50 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.391527E-6).
• BP6: Variant 17-82905981-T-C is Benign according to our data. Variant chr17-82905981-T-C is described in ClinVar as Benign. ClinVar VariationId is 1167401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.65 is higher than 0.05.

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.1850T>C	p.Met617Thr	missense	Exon 20 of 39	NP_005984.3
	TBCD	NM_001411101.1		c.1799T>C	p.Met600Thr	missense	Exon 19 of 38	NP_001398030.1	A0A804HLI2
	TBCD	NM_001411102.1		c.1769T>C	p.Met590Thr	missense	Exon 19 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.1850T>C	p.Met617Thr	missense	Exon 20 of 39	ENSP00000347719.4	Q9BTW9-1
	TBCD	ENST00000571316.5	TSL:1	c.368T>C	p.Met123Thr	missense	Exon 6 of 11	ENSP00000458365.1	I3L0V3
	TBCD	ENST00000571796.5	TSL:1	n.367T>C		non_coding_transcript_exon	Exon 4 of 17

Frequencies

GnomAD3 genomes AF: 0.485 AC: 73650 AN: 151994 Hom.: 18812 Cov.: 34

Gnomad AFR AF: 0.656

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.488

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.538

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.468

GnomAD2 exomes AF: 0.438 AC: 107922 AN: 246480 AF XY: 0.443

Gnomad AFR exome AF: 0.662

Gnomad AMR exome AF: 0.373

Gnomad ASJ exome AF: 0.483

Gnomad EAS exome AF: 0.270

Gnomad FIN exome AF: 0.414

Gnomad NFE exome AF: 0.427

Gnomad OTH exome AF: 0.446

GnomAD4 exome AF: 0.433 AC: 629770 AN: 1455528 Hom.: 138815 Cov.: 44 AF XY: 0.435 AC XY: 315065 AN XY: 723978

African (AFR) AF: 0.667 AC: 22224 AN: 33300

American (AMR) AF: 0.383 AC: 17029 AN: 44446

Ashkenazi Jewish (ASJ) AF: 0.484 AC: 12638 AN: 26110

East Asian (EAS) AF: 0.258 AC: 10215 AN: 39644

South Asian (SAS) AF: 0.536 AC: 46075 AN: 85890

European-Finnish (FIN) AF: 0.416 AC: 22097 AN: 53152

Middle Eastern (MID) AF: 0.538 AC: 3098 AN: 5760

European-Non Finnish (NFE) AF: 0.424 AC: 469439 AN: 1107036

Other (OTH) AF: 0.448 AC: 26955 AN: 60190

GnomAD4 genome AF: 0.485 AC: 73705 AN: 152112 Hom.: 18827 Cov.: 34 AF XY: 0.482 AC XY: 35822 AN XY: 74356

African (AFR) AF: 0.656 AC: 27221 AN: 41488

American (AMR) AF: 0.414 AC: 6334 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.488 AC: 1694 AN: 3468

East Asian (EAS) AF: 0.287 AC: 1486 AN: 5172

South Asian (SAS) AF: 0.537 AC: 2593 AN: 4828

European-Finnish (FIN) AF: 0.408 AC: 4317 AN: 10574

Middle Eastern (MID) AF: 0.527 AC: 154 AN: 292

European-Non Finnish (NFE) AF: 0.422 AC: 28699 AN: 67970

Other (OTH) AF: 0.464 AC: 981 AN: 2114

Alfa AF: 0.444 Hom.: 52735

Bravo AF: 0.491

TwinsUK AF: 0.426 AC: 1579

ALSPAC AF: 0.423 AC: 1630

ESP6500AA AF: 0.674 AC: 2857

ESP6500EA AF: 0.431 AC: 3645

ExAC AF: 0.447 AC: 54064

Asia WGS AF: 0.448 AC: 1555 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.13
DANN	Benign	0.21
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0028	N
LIST_S2	Benign	0.023	T
MetaRNN	Benign	0.0000044	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.3	N
PhyloP100		0.11
PrimateAI	Benign	0.35	T
PROVEAN	Benign	2.8	N
REVEL	Benign	0.094
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.10
MPC		0.33
ClinPred		0.0024	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.014
gMVP		0.15
Mutation Taster		=99/1	polymorphism (auto)

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: rs2292971; hg19: chr17-80863857; COSMIC: COSV62797771; COSMIC: COSV62797771;