9-98200284-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001267571.2(TBC1D2):c.2548C>T(p.Arg850Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00363 in 1,613,882 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (26 hom.)
• Consequence: TBC1D2 NM_001267571.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.62

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016935587).
• BP6: Variant 9-98200284-G-A is Benign according to our data. Variant chr9-98200284-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 710851.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D2	NM_001267571.2	c.2548C>T	p.Arg850Cys	missense_variant	12/13	ENST00000465784.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D2	ENST00000465784.7	c.2548C>T	p.Arg850Cys	missense_variant	12/13	1	NM_001267571.2	P2

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 453 AN: 151972 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00407

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00213

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00409

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00337 AC: 847 AN: 251330 Hom.: 6 AF XY: 0.00329 AC XY: 447 AN XY: 135842

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.00114

Gnomad SAS exome AF: 0.00468

Gnomad FIN exome AF: 0.00231

Gnomad NFE exome AF: 0.00411

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00370 AC: 5403 AN: 1461792 Hom.: 26 Cov.: 34 AF XY: 0.00368 AC XY: 2679 AN XY: 727186

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00239

Gnomad4 ASJ exome AF: 0.00375

Gnomad4 EAS exome AF: 0.000605

Gnomad4 SAS exome AF: 0.00537

Gnomad4 FIN exome AF: 0.00221

Gnomad4 NFE exome AF: 0.00383

Gnomad4 OTH exome AF: 0.00401

GnomAD4 genome AF: 0.00298 AC: 453 AN: 152090 Hom.: 5 Cov.: 32 AF XY: 0.00281 AC XY: 209 AN XY: 74348

Gnomad4 AFR AF: 0.000723

Gnomad4 AMR AF: 0.00406

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00213

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.00236

Gnomad4 NFE AF: 0.00409

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00392 Hom.: 4

Bravo AF: 0.00274

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00329 AC: 399

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00528

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jun 18, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.19	T;.;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.017	T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Pathogenic	3.0	M;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.31	T
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;.;.;.;D
Vest4		0.65
MVP		0.63
MPC		1.1
ClinPred		0.10	T
GERP RS		4.5
Varity_R		0.69
gMVP		0.62

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: rs137868712; hg19: chr9-100962566; COSMIC: COSV59785498;