NM_144572.2:c.2798C>T

Variant names:

• chr15-77998254-G-A
• rs367930643
• NM_144572.2:c.2798C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS1

The NM_144572.2(TBC1D2B):​c.2798C>T​(p.Thr933Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000165 in 1,598,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: TBC1D2B NM_144572.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.96
• Publications: 0 publications found

Genes affected

TBC1D2B (HGNC:29183): (TBC1 domain family member 2B) Predicted to enable GTPase activator activity. Predicted to be involved in activation of GTPase activity and intracellular protein transport. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

TBC1D2B Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with seizures and gingival overgrowth

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1664786).
• BP6: Variant 15-77998254-G-A is Benign according to our data. Variant chr15-77998254-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3453488.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000394 (6/152224) while in subpopulation NFE AF = 0.0000882 (6/68038). AF 95% confidence interval is 0.0000376. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144572.2. 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
	TBC1D2B	NM_144572.2	MANE Select	c.2798C>T	p.Thr933Ile	missense	Exon 13 of 13	NP_653173.1	Q9UPU7-1
	TBC1D2B	NM_001387142.1		c.2798C>T	p.Thr933Ile	missense	Exon 13 of 14	NP_001374071.1
	TBC1D2B	NM_001387143.1		c.2795C>T	p.Thr932Ile	missense	Exon 13 of 13	NP_001374072.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D2B	ENST00000300584.8	TSL:5 MANE Select	c.2798C>T	p.Thr933Ile	missense	Exon 13 of 13	ENSP00000300584.3	Q9UPU7-1
	TBC1D2B	ENST00000409931.7	TSL:1	c.*1C>T		3_prime_UTR	Exon 13 of 13	ENSP00000387165.3	Q9UPU7-2
	TBC1D2B	ENST00000936499.1		c.2801C>T	p.Thr934Ile	missense	Exon 13 of 13	ENSP00000606558.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152224 Hom.: 0 Cov.: 33

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000266 AC: 6 AN: 225336 AF XY: 0.0000247

Gnomad AFR exome AF: 0.0000737

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000395

Gnomad OTH exome AF: 0.000176

GnomAD4 exome AF: 0.000178 AC: 257 AN: 1445848 Hom.: 0 Cov.: 30 AF XY: 0.000176 AC XY: 126 AN XY: 717536

African (AFR) AF: 0.0000302 AC: 1 AN: 33162

American (AMR) AF: 0.00 AC: 0 AN: 42188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25810

East Asian (EAS) AF: 0.00 AC: 0 AN: 38768

South Asian (SAS) AF: 0.00 AC: 0 AN: 83162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.000230 AC: 254 AN: 1105164

Other (OTH) AF: 0.0000334 AC: 2 AN: 59860

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.046
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.0
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.050
Sift	Benign	0.070	T
Sift4G	Benign	0.24	T
Polyphen		0.29	B
Vest4		0.33
MVP		0.43
MPC		0.69
ClinPred		0.11	T
GERP RS		4.5
Varity_R		0.090
gMVP		0.35
Mutation Taster		=79/21	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: rs367930643; hg19: chr15-78290596;