15-78001706-T-C

Variant names:

• chr15-78001706-T-C
• NM_144572.2:c.2609A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_144572.2(TBC1D2B):​c.2609A>G​(p.Tyr870Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,426 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TBC1D2B NM_144572.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.01

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D2B	NM_144572.2	c.2609A>G	p.Tyr870Cys	missense_variant	Exon 12 of 13	ENST00000300584.8	NP_653173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D2B	ENST00000300584.8	c.2609A>G	p.Tyr870Cys	missense_variant	Exon 12 of 13	5	NM_144572.2	ENSP00000300584.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456426 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 723834

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2609A>G (p.Y870C) alteration is located in exon 12 (coding exon 12) of the TBC1D2B gene. This alteration results from a A to G substitution at nucleotide position 2609, causing the tyrosine (Y) at amino acid position 870 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Benign	0.17
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.73	P;P
Vest4		0.66
MutPred		0.45		Gain of methylation at K869 (P = 0.0151);Gain of methylation at K869 (P = 0.0151);
MVP		0.56
MPC		1.1
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.73
gMVP		0.59

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-78294048;