chr11-67405119-C-G

Variant names:

• chr11-67405119-C-G
• rs147100387
• NM_001369496.1:c.187C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001369496.1(TBC1D10C):​c.187C>G​(p.Arg63Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,399,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R63W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TBC1D10C NM_001369496.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0200
• Publications: 1 publications found

Genes affected

TBC1D10C (HGNC:24702): (TBC1 domain family member 10C) The protein encoded by this gene has an N-terminal Rab-GTPase domain and a binding site at the C-terminus for calcineurin, and is an inhibitor of both the Ras signaling pathway and calcineurin, a phosphatase regulated by calcium and calmodulin. Genes encoding similar proteins are located on chromosomes 16 and 22. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2013]

PPP1CA (HGNC:9281): (protein phosphatase 1 catalytic subunit alpha) The protein encoded by this gene is one of the three catalytic subunits of protein phosphatase 1 (PP1). This broadly expressed gene encodes the alpha subunit of the PP1 complex that associates with over 200 regulatory proteins to form holoenzymes which dephosphorylate their biological targets with high specificity. PP1 is a serine/threonine specific protein phosphatase known to be involved in the regulation of a variety of cellular processes, such as cell division, glycogen metabolism, muscle contractility, protein synthesis, and HIV-1 viral transcription. Increased PP1 activity has been observed in the end stage of heart failure. Studies suggest that PP1 is an important regulator of cardiac function and that PP1 deregulation is implicated in diabetes and multiple types of cancer. Three alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2020]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35067788).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369496.1. 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
	TBC1D10C	NM_001369496.1	MANE Select	c.187C>G	p.Arg63Gly	missense	Exon 2 of 9	NP_001356425.1	Q8IV04-1
	TBC1D10C	NM_001369498.1		c.187C>G	p.Arg63Gly	missense	Exon 2 of 9	NP_001356427.1
	TBC1D10C	NM_001369497.1		c.187C>G	p.Arg63Gly	missense	Exon 3 of 10	NP_001356426.1	Q8IV04-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D10C	ENST00000542590.2	TSL:1 MANE Select	c.187C>G	p.Arg63Gly	missense	Exon 2 of 9	ENSP00000443654.1	Q8IV04-1
	TBC1D10C	ENST00000946012.1		c.187C>G	p.Arg63Gly	missense	Exon 2 of 9	ENSP00000616071.1
	TBC1D10C	ENST00000868931.1		c.187C>G	p.Arg63Gly	missense	Exon 3 of 10	ENSP00000538990.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1399090 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 690058

African (AFR) AF: 0.00 AC: 0 AN: 31602

American (AMR) AF: 0.00 AC: 0 AN: 35708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.0000839 AC: 3 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078918

Other (OTH) AF: 0.00 AC: 0 AN: 57996

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		0.020
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.85	P
Vest4		0.58
MutPred		0.56		Loss of catalytic residue at R63 (P = 0.0206)
MVP		0.58
MPC		0.88
ClinPred		0.98	D
GERP RS		3.1
Varity_R		0.79
gMVP		0.86
Mutation Taster		=44/56	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147100387; hg19: chr11-67172590;