9-98208713-A-T

Variant summary

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

The NM_001267571.2(TBC1D2):c.2105T>A(p.Phe702Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000935 in 1,390,856 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: 0.0000093 (0 hom.)
• Consequence: TBC1D2 NM_001267571.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.88

Genes affected

TBC1D2 (HGNC:18026): (TBC1 domain family member 2) Enables GTPase activator activity and cadherin binding activity. Involved in positive regulation of GTPase activity. Located in several cellular components, including cytoplasmic vesicle; cytosol; and nucleoplasm. [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/exons	MANE	UniProt
TBC1D2	NM_001267571.2	c.2105T>A	p.Phe702Tyr	missense_variant	9/13	ENST00000465784.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D2	ENST00000465784.7	c.2105T>A	p.Phe702Tyr	missense_variant	9/13	1	NM_001267571.2	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000935 AC: 13 AN: 1390856 Hom.: 0 Cov.: 31 AF XY: 0.00000732 AC XY: 5 AN XY: 682738

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: 0.0000121

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2022

The c.2105T>A (p.F702Y) alteration is located in exon 9 (coding exon 9) of the TBC1D2 gene. This alteration results from a T to A substitution at nucleotide position 2105, causing the phenylalanine (F) at amino acid position 702 to be replaced by a tyrosine (Y). 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	0.26
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.017	T;.;.;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.76	T;T;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.47	T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.13	N;.;N;.;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
Sift4G	Benign	0.21	T;T;T;T;T
Polyphen		1.0	D;.;.;.;D
Vest4		0.55
MutPred		0.76		Loss of stability (P = 0.1821);.;Loss of stability (P = 0.1821);.;Loss of stability (P = 0.1821);
MVP		0.54
MPC		1.0
ClinPred		0.92	D
GERP RS		5.8
Varity_R		0.26
gMVP		0.73

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

LitVar

Other links and lift over

dbSNP: rs1722039456; hg19: chr9-100970995;