rs144284088

Variant names:

• chr15-77998221-C-T
• rs144284088
• NM_144572.2:c.2831G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-77998221-C-T
• chr15-77998221-C-A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_144572.2(TBC1D2B):​c.2831G>A​(p.Arg944His) variant causes a missense change. The variant allele was found at a frequency of 0.0000369 in 1,570,236 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: TBC1D2B NM_144572.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.71
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013137251).

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.2831G>A	p.Arg944His	missense	Exon 13 of 13	NP_653173.1	Q9UPU7-1
	TBC1D2B	NM_001387142.1		c.2831G>A	p.Arg944His	missense	Exon 13 of 14	NP_001374071.1
	TBC1D2B	NM_001387143.1		c.2828G>A	p.Arg943His	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.2831G>A	p.Arg944His	missense	Exon 13 of 13	ENSP00000300584.3	Q9UPU7-1
	TBC1D2B	ENST00000409931.7	TSL:1	c.*34G>A		3_prime_UTR	Exon 13 of 13	ENSP00000387165.3	Q9UPU7-2
	TBC1D2B	ENST00000936499.1		c.2834G>A	p.Arg945His	missense	Exon 13 of 13	ENSP00000606558.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152232 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000169 AC: 32 AN: 189178 AF XY: 0.000149

Gnomad AFR exome AF: 0.000631

Gnomad AMR exome AF: 0.000257

Gnomad ASJ exome AF: 0.000568

Gnomad EAS exome AF: 0.0000737

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000111

Gnomad OTH exome AF: 0.000394

GnomAD4 exome AF: 0.0000402 AC: 57 AN: 1418004 Hom.: 0 Cov.: 30 AF XY: 0.0000442 AC XY: 31 AN XY: 701332

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

African (AFR) AF: 0.000278 AC: 9 AN: 32358

American (AMR) AF: 0.000186 AC: 7 AN: 37654

Ashkenazi Jewish (ASJ) AF: 0.000239 AC: 6 AN: 25134

East Asian (EAS) AF: 0.00 AC: 0 AN: 37252

South Asian (SAS) AF: 0.0000249 AC: 2 AN: 80260

European-Finnish (FIN) AF: 0.0000396 AC: 2 AN: 50464

Middle Eastern (MID) AF: 0.000704 AC: 4 AN: 5682

European-Non Finnish (NFE) AF: 0.0000238 AC: 26 AN: 1090340

Other (OTH) AF: 0.0000170 AC: 1 AN: 58860

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000509 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.000283 AC: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	Benign	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.055
Eigen_PC	Benign	-0.062
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.15
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.34
MVP		0.45
MPC		1.0
ClinPred		0.058	T
GERP RS		3.6
Varity_R		0.070
gMVP		0.40
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs144284088; hg19: chr15-78290563;