15-78003423-T-C

Position:

• chr15-78003423-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_144572.2(TBC1D2B):​c.2456A>G​(p.Gln819Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00159 in 1,613,502 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (11 hom.)
• Consequence: TBC1D2B NM_144572.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.10

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009497255).
• BP6: Variant 15-78003423-T-C is Benign according to our data. Variant chr15-78003423-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 713527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00295 (449/152320) while in subpopulation AFR AF= 0.00486 (202/41566). AF 95% confidence interval is 0.00431. There are 3 homozygotes in gnomad4. There are 224 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D2B	NM_144572.2	c.2456A>G	p.Gln819Arg	missense_variant	11/13	ENST00000300584.8	NP_653173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBC1D2B	ENST00000300584.8	c.2456A>G	p.Gln819Arg	missense_variant	11/13	5	NM_144572.2	ENSP00000300584.3
TBC1D2B	ENST00000409931.7	c.2456A>G	p.Gln819Arg	missense_variant	11/13	1		ENSP00000387165.3
TBC1D2B	ENST00000472786.1	n.1422A>G		non_coding_transcript_exon_variant	4/4	2
TBC1D2B	ENST00000497942.1	n.157A>G		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 450 AN: 152200 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00490

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00225 AC: 565 AN: 250834 Hom.: 3 AF XY: 0.00218 AC XY: 296 AN XY: 135576

Gnomad AFR exome AF: 0.00455

Gnomad AMR exome AF: 0.00296

Gnomad ASJ exome AF: 0.0138

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00203

Gnomad NFE exome AF: 0.00156

Gnomad OTH exome AF: 0.00409

GnomAD4 exome AF: 0.00144 AC: 2109 AN: 1461182 Hom.: 11 Cov.: 31 AF XY: 0.00143 AC XY: 1041 AN XY: 726806

Gnomad4 AFR exome AF: 0.00338

Gnomad4 AMR exome AF: 0.00338

Gnomad4 ASJ exome AF: 0.0168

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00208

Gnomad4 NFE exome AF: 0.000919

Gnomad4 OTH exome AF: 0.00353

GnomAD4 genome AF: 0.00295 AC: 449 AN: 152320 Hom.: 3 Cov.: 32 AF XY: 0.00301 AC XY: 224 AN XY: 74482

Gnomad4 AFR AF: 0.00486

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.0158

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.00140

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00216 Hom.: 4

Bravo AF: 0.00298

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00433 AC: 19

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00182 AC: 221

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 16, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	TBC1D2B: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.011	T;.
Eigen	Benign	0.012
Eigen_PC	Benign	0.021
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.0095	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.97	L;L
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.20
Sift	Uncertain	0.015	D;D
Sift4G	Benign	0.14	T;T
Polyphen		0.64	P;P
Vest4		0.59
MVP		0.42
MPC		0.88
ClinPred		0.013	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs138988358; hg19: chr15-78295765;