Genetic Variant TMTC2:p.Tyr317Cys (chr12-82896113-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_152588.3(TMTC2):c.950A>G(p.Tyr317Cys) variant causes a missense change involving the alteration of a 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y317S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

TMTC2
NM_152588.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.95

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
hearing loss, autosomal recessive 122
Inheritance: AR Classification: NO_KNOWN Submitted by: PanelApp Australia

TMTC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.961

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152588.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMTC2	NM_152588.3	MANE Select	c.950A>G	p.Tyr317Cys	missense	Exon 3 of 12	NP_689801.1	Q8N394
TMTC2	NM_001320322.2		c.950A>G	p.Tyr317Cys	missense	Exon 3 of 6	NP_001307251.1	F8VSH2
TMTC2	NM_001320321.2		c.215A>G	p.Tyr72Cys	missense	Exon 2 of 11	NP_001307250.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMTC2	ENST00000321196.8	TSL:1 MANE Select	c.950A>G	p.Tyr317Cys	missense	Exon 3 of 12	ENSP00000322300.3	Q8N394
TMTC2	ENST00000549919.1	TSL:1	c.932A>G	p.Tyr311Cys	missense	Exon 4 of 13	ENSP00000447609.1	A0A0B4J253
TMTC2	ENST00000548305.5	TSL:1	c.950A>G	p.Tyr317Cys	missense	Exon 3 of 6	ENSP00000448292.1	F8VSH2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

-0.23

MutationAssessor

Pathogenic

3.3

PhyloP100

8.9

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-7.9

REVEL

Uncertain

0.58

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.88

MutPred

0.82

Loss of helix (P = 0.1706)

MVP

0.34

MPC

0.73

ClinPred

1.0

GERP RS

6.0

Varity_R

0.86

gMVP

0.73

Mutation Taster

=34/66

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over