Variant chr12-47964286-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001143842.2(TMEM106C):c.50A>C(p.Lys17Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,613,964 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

TMEM106C
NM_001143842.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.526

Variant links:

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]

TMEM106C links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.027323484).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM106C	NM_001143842.2 link	c.50A>C	p.Lys17Thr	missense_variant	2/8	ENST00000429772.7	NP_001137314.1	Q9BVX2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMEM106C	ENST00000429772.7 link	c.50A>C	p.Lys17Thr	missense_variant	2/8	2	NM_001143842.2	ENSP00000400471.2	Q9BVX2-1
TMEM106C	ENST00000552546.5 link	c.50A>C	p.Lys17Thr	missense_variant	2/7	4		ENSP00000448268.1	C9JUY7
TMEM106C	ENST00000548640.5 link	c.50A>C	p.Lys17Thr	missense_variant	2/7	3		ENSP00000447254.1	F8W001

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000717

AC:

AN:

250990

Hom.:

AF XY:

0.0000664

AC XY:

AN XY:

135640

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000655

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000486

AC:

AN:

1461750

Hom.:

Cov.:

AF XY:

0.0000605

AC XY:

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00111

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.000102

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2024

The c.50A>C (p.K17T) alteration is located in exon 2 (coding exon 1) of the TMEM106C gene. This alteration results from a A to C substitution at nucleotide position 50, causing the lysine (K) at amino acid position 17 to be replaced by a threonine (T). 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

0.12

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.79

DEOGEN2

Benign

0.024

.;T;T;.;.;T;.;.;.

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.77

.;T;.;T;.;T;T;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.027

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.5

L;.;L;.;L;L;.;L;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.31

N;N;N;N;N;N;.;N;N

REVEL

Benign

0.051

Sift

Benign

0.068

T;D;T;D;T;T;.;T;D

Sift4G

Benign

0.27

T;T;T;D;T;T;T;T;D

Polyphen

0.28

B;.;B;.;B;B;.;B;.

Vest4

0.15

MutPred

0.20

Loss of ubiquitination at K17 (P = 0.0012);Loss of ubiquitination at K17 (P = 0.0012);Loss of ubiquitination at K17 (P = 0.0012);Loss of ubiquitination at K17 (P = 0.0012);Loss of ubiquitination at K17 (P = 0.0012);Loss of ubiquitination at K17 (P = 0.0012);Loss of ubiquitination at K17 (P = 0.0012);Loss of ubiquitination at K17 (P = 0.0012);Loss of ubiquitination at K17 (P = 0.0012);

MVP

0.14

MPC

0.41

ClinPred

0.041

GERP RS

-1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.068

gMVP

0.36

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over