chr12-83029561-A-G

Variant names:

• chr12-83029561-A-G
• rs17740709
• NM_152588.3:c.2071-1237A>G

Variant summary

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

The NM_152588.3(TMTC2):​c.2071-1237A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 152,176 control chromosomes in the GnomAD database, including 2,675 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 0.19 (2675 hom., cov: 32)
• Consequence: TMTC2 NM_152588.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18
• Publications: 4 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMTC2	NM_152588.3	c.2071-1237A>G		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.2071-1237A>G		intron_variant	Intron 8 of 11	1	NM_152588.3	ENSP00000322300.3
TMTC2	ENST00000549919.1	c.2053-1237A>G		intron_variant	Intron 9 of 12	1		ENSP00000447609.1
TMTC2	ENST00000546590.2	n.*1392-1237A>G		intron_variant	Intron 7 of 10	1		ENSP00000448630.2

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28217 AN: 152058 Hom.: 2672 Cov.: 32

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.0629

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.203

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

GnomAD4 genome AF: 0.186 AC: 28233 AN: 152176 Hom.: 2675 Cov.: 32 AF XY: 0.182 AC XY: 13530 AN XY: 74414

African (AFR) AF: 0.167 AC: 6936 AN: 41520

American (AMR) AF: 0.203 AC: 3094 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 861 AN: 3470

East Asian (EAS) AF: 0.0621 AC: 322 AN: 5188

South Asian (SAS) AF: 0.155 AC: 748 AN: 4830

European-Finnish (FIN) AF: 0.150 AC: 1587 AN: 10604

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14061 AN: 67982

Other (OTH) AF: 0.204 AC: 430 AN: 2112

Alfa AF: 0.202 Hom.: 13103

Bravo AF: 0.191

Asia WGS AF: 0.130 AC: 454 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.15
DANN	Benign	0.74
PhyloP100		-1.2
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: rs17740709; hg19: chr12-83423340;