NM_015188.2:c.254T>C

Variant names:

• chr10-94402867-T-C
• NM_015188.2:c.254T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015188.2(TBC1D12):​c.254T>C​(p.Leu85Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBC1D12 NM_015188.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.91
• Publications: 0 publications found

Genes affected

TBC1D12 (HGNC:29082): (TBC1 domain family member 12) Predicted to enable GTPase activator activity. Predicted to be involved in activation of GTPase activity; intracellular protein transport; and regulation of autophagosome assembly. Predicted to be active in autophagosome and recycling endosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19506887).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015188.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D12	NM_015188.2	MANE Select	c.254T>C	p.Leu85Pro	missense	Exon 1 of 13	NP_056003.1	O60347

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D12	ENST00000225235.5	TSL:1 MANE Select	c.254T>C	p.Leu85Pro	missense	Exon 1 of 13	ENSP00000225235.4	O60347
	TBC1D12	ENST00000971288.1		c.254T>C	p.Leu85Pro	missense	Exon 1 of 12	ENSP00000641347.1
	TBC1D12	ENST00000904400.1		c.254T>C	p.Leu85Pro	missense	Exon 1 of 12	ENSP00000574459.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1366786 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 672712

African (AFR) AF: 0.00 AC: 0 AN: 29114

American (AMR) AF: 0.00 AC: 0 AN: 32042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23144

East Asian (EAS) AF: 0.00 AC: 0 AN: 34258

South Asian (SAS) AF: 0.00 AC: 0 AN: 74838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4828

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1068354

Other (OTH) AF: 0.00 AC: 0 AN: 56688

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.063
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.024	B
Vest4		0.34
MutPred		0.18		Loss of sheet (P = 0.0181)
MVP		0.36
MPC		1.8
ClinPred		0.84	D
GERP RS		3.5
PromoterAI		0.18	Neutral
Varity_R		0.29
gMVP		0.31
Mutation Taster		=71/29	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

hg19: chr10-96162624;