9-98203353-G-C

Variant names:

• chr9-98203353-G-C
• rs376426928
• NM_001267571.2:c.2206C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001267571.2(TBC1D2):​c.2206C>G​(p.Leu736Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,614,124 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: TBC1D2 NM_001267571.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.97
• Publications: 0 publications found

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]

ENSG00000299446 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D2	NM_001267571.2	c.2206C>G	p.Leu736Val	missense_variant	Exon 10 of 13	ENST00000465784.7	NP_001254500.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D2	ENST00000465784.7	c.2206C>G	p.Leu736Val	missense_variant	Exon 10 of 13	1	NM_001267571.2	ENSP00000481721.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152242 Hom.: 1 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: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251382 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000280 AC: 41 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.000480 AC: 29 AN: 60396

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152242 Hom.: 1 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74382

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

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000770 AC: 4 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2206C>G (p.L736V) alteration is located in exon 10 (coding exon 10) of the TBC1D2 gene. This alteration results from a C to G substitution at nucleotide position 2206, causing the leucine (L) at amino acid position 736 to be replaced by a valine (V). 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	0.22
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	4.2	H;.;H;.;H
PhyloP100		3.0
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.0	.;D;D;D;D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;.;.;.;D
Vest4		0.81
MutPred		0.65		Gain of glycosylation at S731 (P = 0.2348);.;Gain of glycosylation at S731 (P = 0.2348);.;Gain of glycosylation at S731 (P = 0.2348);
MVP		0.56
MPC		0.98
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.14
gMVP		0.79
Mutation Taster		=69/31	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: rs376426928; hg19: chr9-100965635;