Variant 12-82896071-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_152588.3(TMTC2):c.908A>G(p.Lys303Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,613,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

TMTC2
NM_152588.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.95

Variant links:

Genes affected

TMTC2 (HGNC:25440): (transmembrane O-mannosyltransferase targeting cadherins 2) The protein encoded by this gene is an integral membrane protein localized to the endoplasmic reticulum (ER). The encoded protein contains many tetratricopeptide repeats, sequences known for being involved in protein-protein interactions. This protein binds both the calcium uptake pump SERCA2B and the carbohydrate-binding chaperone calnexin, and it appears to play a role in calcium homeostasis in the ER. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

TMTC2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.016506553).

BP6

Variant 12-82896071-A-G is Benign according to our data. Variant chr12-82896071-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3054671.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMTC2	NM_152588.3 linkuse as main transcript	c.908A>G	p.Lys303Arg	missense_variant	3/12	ENST00000321196.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMTC2	ENST00000321196.8 linkuse as main transcript	c.908A>G	p.Lys303Arg	missense_variant	3/12	1	NM_152588.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000243

AC:

AN:

251464

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00176

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000479

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00154

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151968

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74204

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000328

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000132

ExAC

AF:

0.000214

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

TMTC2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.56

Cadd

Benign

Dann

Benign

0.25

DEOGEN2

Benign

0.0013

T;.;T

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.0028

MetaRNN

Benign

0.017

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.32

N;.;.

MutationTaster

Benign

0.98

D;D;D;D

PrimateAI

Benign

0.47

PROVEAN

Benign

0.61

N;N;N

REVEL

Benign

0.048

Sift

Benign

0.82

T;T;T

Sift4G

Benign

0.84

T;T;T

Polyphen

0.0030

B;B;.

Vest4

0.13

MutPred

0.68

Loss of ubiquitination at K303 (P = 0.0218);Loss of ubiquitination at K303 (P = 0.0218);.;

MVP

0.19

MPC

0.12

ClinPred

0.0066

GERP RS

2.4

Varity_R

0.087

gMVP

0.32

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

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