rs7298326

Variant names:

• chr12-83131459-A-G
• rs7298326
• NM_152588.3:c.2332-751A>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.2332-751A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 152,066 control chromosomes in the GnomAD database, including 6,999 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 0.29 (6999 hom., cov: 33)
• Consequence: TMTC2 NM_152588.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.374
• 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMTC2	NM_152588.3	MANE Select	c.2332-751A>G		intron	N/A	NP_689801.1
	TMTC2	NM_001320321.2		c.1597-751A>G		intron	N/A	NP_001307250.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMTC2	ENST00000321196.8	TSL:1 MANE Select	c.2332-751A>G		intron	N/A	ENSP00000322300.3
	TMTC2	ENST00000549919.1	TSL:1	c.2314-751A>G		intron	N/A	ENSP00000447609.1
	TMTC2	ENST00000546590.2	TSL:1	n.*1653-751A>G		intron	N/A	ENSP00000448630.2

Frequencies

GnomAD3 genomes AF: 0.293 AC: 44566 AN: 151946 Hom.: 6990 Cov.: 33

Gnomad AFR AF: 0.395

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.273

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

GnomAD4 genome AF: 0.293 AC: 44609 AN: 152066 Hom.: 6999 Cov.: 33 AF XY: 0.290 AC XY: 21597 AN XY: 74350

African (AFR) AF: 0.395 AC: 16372 AN: 41470

American (AMR) AF: 0.204 AC: 3125 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 720 AN: 3466

East Asian (EAS) AF: 0.326 AC: 1690 AN: 5186

South Asian (SAS) AF: 0.329 AC: 1586 AN: 4822

European-Finnish (FIN) AF: 0.288 AC: 3040 AN: 10566

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.253 AC: 17197 AN: 67966

Other (OTH) AF: 0.276 AC: 582 AN: 2108

Alfa AF: 0.280 Hom.: 831

Bravo AF: 0.292

Asia WGS AF: 0.324 AC: 1124 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	14
DANN	Benign	0.77
PhyloP100		0.37
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: rs7298326; hg19: chr12-83525238;