9-98199422-C-T

Variant names:

• chr9-98199422-C-T
• rs34769888
• NM_001267571.2:c.2746G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001267571.2(TBC1D2):​c.2746G>A​(p.Glu916Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00699 in 1,613,802 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0071 (44 hom.)
• Consequence: TBC1D2 NM_001267571.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.450
• Publications: 9 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003650248).
• BP6: Variant 9-98199422-C-T is Benign according to our data. Variant chr9-98199422-C-T is described in ClinVar as [Benign]. Clinvar id is 770388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D2	NM_001267571.2	c.2746G>A	p.Glu916Lys	missense_variant	Exon 13 of 13	ENST00000465784.7	NP_001254500.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D2	ENST00000465784.7	c.2746G>A	p.Glu916Lys	missense_variant	Exon 13 of 13	1	NM_001267571.2	ENSP00000481721.1

Frequencies

GnomAD3 genomes AF: 0.00597 AC: 909 AN: 152174 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00392

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00813

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00755 AC: 1894 AN: 250816 AF XY: 0.00823

Gnomad AFR exome AF: 0.00204

Gnomad AMR exome AF: 0.00411

Gnomad ASJ exome AF: 0.0175

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00758

Gnomad NFE exome AF: 0.00850

Gnomad OTH exome AF: 0.00751

GnomAD4 exome AF: 0.00710 AC: 10379 AN: 1461510 Hom.: 44 Cov.: 31 AF XY: 0.00741 AC XY: 5384 AN XY: 727068

African (AFR) AF: 0.00125 AC: 42 AN: 33468

American (AMR) AF: 0.00418 AC: 187 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 482 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0119 AC: 1025 AN: 86242

European-Finnish (FIN) AF: 0.00714 AC: 381 AN: 53346

Middle Eastern (MID) AF: 0.0154 AC: 86 AN: 5570

European-Non Finnish (NFE) AF: 0.00695 AC: 7731 AN: 1111982

Other (OTH) AF: 0.00734 AC: 443 AN: 60350

GnomAD4 genome AF: 0.00596 AC: 908 AN: 152292 Hom.: 5 Cov.: 33 AF XY: 0.00584 AC XY: 435 AN XY: 74464

African (AFR) AF: 0.00178 AC: 74 AN: 41558

American (AMR) AF: 0.00392 AC: 60 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 73 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.0151 AC: 73 AN: 4828

European-Finnish (FIN) AF: 0.00565 AC: 60 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00813 AC: 553 AN: 68014

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00763 Hom.: 12

Bravo AF: 0.00527

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00930 AC: 80

ExAC AF: 0.00773 AC: 938

Asia WGS AF: 0.00318 AC: 13 AN: 3478

EpiCase AF: 0.00938

EpiControl AF: 0.00901

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jun 14, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TBC1D2: BP4, BS1, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0067	T;.;.;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.74	T;T;T;T
MetaRNN	Benign	0.0037	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.3	M;.;.;.
PhyloP100		0.45
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.3	.;N;N;N
REVEL	Benign	0.028
Sift	Uncertain	0.016	.;D;D;D
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.31	B;.;.;B
Vest4		0.092
MVP		0.37
MPC		0.34
ClinPred		0.012	T
GERP RS		3.5
Varity_R		0.048
gMVP		0.31
Mutation Taster		=97/3	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: rs34769888; hg19: chr9-100961704;