11-67406963-G-A

Position:

• chr11-67406963-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001369496.1(TBC1D10C):​c.785G>A​(p.Arg262His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000986 in 1,613,172 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: TBC1D10C NM_001369496.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.65

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D10C	NM_001369496.1	c.785G>A	p.Arg262His	missense_variant	7/9	ENST00000542590.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D10C	ENST00000542590.2	c.785G>A	p.Arg262His	missense_variant	7/9	1	NM_001369496.1	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000359 AC: 9 AN: 250590 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135594

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000103 AC: 151 AN: 1460896 Hom.: 0 Cov.: 31 AF XY: 0.000107 AC XY: 78 AN XY: 726812

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000128

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74466

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2022

The c.785G>A (p.R262H) alteration is located in exon 8 (coding exon 7) of the TBC1D10C gene. This alteration results from a G to A substitution at nucleotide position 785, causing the arginine (R) at amino acid position 262 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.00091	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.75
MVP		0.57
ClinPred		0.93	D
GERP RS		4.2
Varity_R		0.65
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs200253978; hg19: chr11-67174434;