NM_001143842.2:c.612C>G

Variant names:

• chr12-47967217-C-G
• NM_001143842.2:c.612C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001143842.2(TMEM106C):​c.612C>G​(p.Cys204Trp) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM106C NM_001143842.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.77

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM106C	NM_001143842.2	c.612C>G	p.Cys204Trp	missense_variant	Exon 7 of 8	ENST00000429772.7	NP_001137314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM106C	ENST00000429772.7	c.612C>G	p.Cys204Trp	missense_variant	Exon 7 of 8	2	NM_001143842.2	ENSP00000400471.2
TMEM106C	ENST00000552546.5	c.399C>G	p.Cys133Trp	missense_variant	Exon 6 of 7	4		ENSP00000448268.1
TMEM106C	ENST00000548640.5	c.342C>G	p.Cys114Trp	missense_variant	Exon 6 of 7	3		ENSP00000447254.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.612C>G (p.C204W) alteration is located in exon 7 (coding exon 6) of the TMEM106C gene. This alteration results from a C to G substitution at nucleotide position 612, causing the cysteine (C) at amino acid position 204 to be replaced by a tryptophan (W). 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	0.98
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	.;T;.;.;T;.;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	.;.;D;.;D;D;D
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.2	.;M;.;.;M;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.3	D;D;D;D;D;D;D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;D;D;.
Vest4		0.93
MutPred		0.82		.;Gain of catalytic residue at P207 (P = 0.0254);.;.;Gain of catalytic residue at P207 (P = 0.0254);.;.;
MVP		0.26
MPC		0.88
ClinPred		1.0	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-48361000;