NM_001143842.2:c.46C>G

Variant names:

• chr12-47964282-C-G
• rs751177758
• NM_001143842.2:c.46C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001143842.2(TMEM106C):​c.46C>G​(p.Arg16Gly) 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. 14/21 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)
• Consequence: TMEM106C NM_001143842.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.193

Genes affected

TMEM106C (HGNC:28775): (transmembrane protein 106C) Predicted to be located in endoplasmic reticulum membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07695803).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM106C	NM_001143842.2	c.46C>G	p.Arg16Gly	missense_variant	Exon 2 of 8	ENST00000429772.7	NP_001137314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM106C	ENST00000429772.7	c.46C>G	p.Arg16Gly	missense_variant	Exon 2 of 8	2	NM_001143842.2	ENSP00000400471.2
TMEM106C	ENST00000552546.5	c.46C>G	p.Arg16Gly	missense_variant	Exon 2 of 7	4		ENSP00000448268.1
TMEM106C	ENST00000548640.5	c.46C>G	p.Arg16Gly	missense_variant	Exon 2 of 7	3		ENSP00000447254.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.46C>G (p.R16G) alteration is located in exon 2 (coding exon 1) of the TMEM106C gene. This alteration results from a C to G substitution at nucleotide position 46, causing the arginine (R) at amino acid position 16 to be replaced by a glycine (G). 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	Benign	0.077
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.77
DEOGEN2	Benign	0.025	.;T;T;.;.;T;.;.;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.63	.;T;.;T;.;T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.077	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.0	M;.;M;.;M;M;.;M;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.72	N;N;N;N;N;N;.;N;N
REVEL	Benign	0.053
Sift	Uncertain	0.014	D;D;D;D;D;D;.;D;D
Sift4G	Benign	0.29	T;T;T;D;T;T;T;T;D
Polyphen		0.28	B;.;B;.;B;B;.;B;.
Vest4		0.26
MutPred		0.16		Loss of stability (P = 0.0192);Loss of stability (P = 0.0192);Loss of stability (P = 0.0192);Loss of stability (P = 0.0192);Loss of stability (P = 0.0192);Loss of stability (P = 0.0192);Loss of stability (P = 0.0192);Loss of stability (P = 0.0192);Loss of stability (P = 0.0192);
MVP		0.20
MPC		0.37
ClinPred		0.17	T
GERP RS		2.5
Varity_R		0.13
gMVP		0.34

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: rs751177758; hg19: chr12-48358065;