dbSNP rs143972184: TMTC2:p.Thr18Thr (chr12-82687640-C-T) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_152588.3(TMTC2):c.54C>T(p.Thr18Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000515 in 1,604,872 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00054 ( 7 hom. )

Consequence

TMTC2
NM_152588.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.11

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 12-82687640-C-T is Benign according to our data. Variant chr12-82687640-C-T is described in ClinVar as Benign. ClinVar VariationId is 748483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.11 with no splicing effect.

BS2

High AC in GnomAd4 at 39 AD gene.

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.54C>T	p.Thr18Thr	synonymous	Exon 1 of 12	NP_689801.1	Q8N394
TMTC2	NM_001320322.2		c.54C>T	p.Thr18Thr	synonymous	Exon 1 of 6	NP_001307251.1	F8VSH2
TMTC2	NM_001320321.2		c.-111C>T		5_prime_UTR	Exon 1 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.54C>T	p.Thr18Thr	synonymous	Exon 1 of 12	ENSP00000322300.3	Q8N394
TMTC2	ENST00000548305.5	TSL:1	c.54C>T	p.Thr18Thr	synonymous	Exon 1 of 6	ENSP00000448292.1	F8VSH2
TMTC2	ENST00000546590.2	TSL:1	n.54C>T		non_coding_transcript_exon	Exon 1 of 11	ENSP00000448630.2	F8VRQ2

Frequencies

GnomAD3 genomes

AF:

0.000257

AC:

AN:

151952

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00417

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000813

AC:

189

AN:

232502

AF XY:

0.00106

show subpopulations

Gnomad AFR exome

AF:

0.0000670

Gnomad AMR exome

AF:

0.0000930

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000588

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000219

Gnomad OTH exome

AF:

0.000529

GnomAD4 exome

AF:

0.000542

AC:

788

AN:

1452802

Hom.:

Cov.:

AF XY:

0.000711

AC XY:

513

AN XY:

721458

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.0000466

AC:

AN:

42920

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25780

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39322

South Asian (SAS)

AF:

0.00595

AC:

498

AN:

83666

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52798

Middle Eastern (MID)

AF:

0.00278

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000216

AC:

240

AN:

1108962

Other (OTH)

AF:

0.000516

AC:

AN:

60134

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

118

157

196

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000256

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41476

American (AMR)

AF:

0.000131

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5160

South Asian (SAS)

AF:

0.00417

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000179

Hom.:

Bravo

AF:

0.000181

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over