rs1682602

Variant names:

• chr12-83012695-T-C
• rs1682602
• NM_152588.3:c.2071-18103T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_152588.3(TMTC2):​c.2071-18103T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.783 in 152,056 control chromosomes in the GnomAD database, including 47,691 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.78 (47691 hom., cov: 32)
• Consequence: TMTC2 NM_152588.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0580
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMTC2	NM_152588.3	c.2071-18103T>C		intron_variant	Intron 8 of 11	ENST00000321196.8	NP_689801.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMTC2	ENST00000321196.8	c.2071-18103T>C		intron_variant	Intron 8 of 11	1	NM_152588.3	ENSP00000322300.3
TMTC2	ENST00000549919.1	c.2053-18103T>C		intron_variant	Intron 9 of 12	1		ENSP00000447609.1
TMTC2	ENST00000546590.2	n.*1392-18103T>C		intron_variant	Intron 7 of 10	1		ENSP00000448630.2

Frequencies

GnomAD3 genomes AF: 0.784 AC: 119048 AN: 151938 Hom.: 47677 Cov.: 32

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.773

Gnomad AMR AF: 0.842

Gnomad ASJ AF: 0.864

Gnomad EAS AF: 0.877

Gnomad SAS AF: 0.928

Gnomad FIN AF: 0.893

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.841

Gnomad OTH AF: 0.811

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.783 AC: 119103 AN: 152056 Hom.: 47691 Cov.: 32 AF XY: 0.791 AC XY: 58778 AN XY: 74310

African (AFR) AF: 0.603 AC: 24980 AN: 41456

American (AMR) AF: 0.842 AC: 12866 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.864 AC: 2997 AN: 3468

East Asian (EAS) AF: 0.877 AC: 4530 AN: 5166

South Asian (SAS) AF: 0.929 AC: 4478 AN: 4820

European-Finnish (FIN) AF: 0.893 AC: 9469 AN: 10608

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.841 AC: 57119 AN: 67938

Other (OTH) AF: 0.812 AC: 1711 AN: 2106

Alfa AF: 0.829 Hom.: 40139

Bravo AF: 0.769

Asia WGS AF: 0.868 AC: 3016 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	9.9
DANN	Benign	0.87
PhyloP100		0.058
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1682602; hg19: chr12-83406474;