rs377646274

Variant names:

• chr9-98208920-C-G
• rs377646274
• NM_001267571.2:c.1898G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-98208920-C-G
• chr9-98208920-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001267571.2(TBC1D2):​c.1898G>C​(p.Arg633Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R633C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TBC1D2 NM_001267571.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.61

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 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
TBC1D2	NM_001267571.2	c.1898G>C	p.Arg633Pro	missense_variant	Exon 9 of 13	ENST00000465784.7	NP_001254500.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D2	ENST00000465784.7	c.1898G>C	p.Arg633Pro	missense_variant	Exon 9 of 13	1	NM_001267571.2	ENSP00000481721.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461842 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T;.;.;.;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.0082
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.87	D;D;D;T;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.44	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.5	M;.;M;.;M
PhyloP100		1.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-4.5	.;D;D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0050	.;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D
Polyphen		1.0	D;.;.;.;D
Vest4		0.53
MutPred		0.55		Gain of catalytic residue at P632 (P = 0.0179);.;Gain of catalytic residue at P632 (P = 0.0179);.;Gain of catalytic residue at P632 (P = 0.0179);
MVP		0.50
MPC		1.2
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.68
gMVP		0.88
Mutation Taster		=64/36	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

Publications

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Other links and lift over

dbSNP: rs377646274; hg19: chr9-100971202;