rs7304787

Variant names:

• chr12-83046851-C-T
• rs7304787
• NM_152588.3:c.2153-4053C>T

Variant summary

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

The NM_152588.3(TMTC2):​c.2153-4053C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0731 in 152,184 control chromosomes in the GnomAD database, including 465 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 0.073 (465 hom., cov: 33)
• Consequence: TMTC2 NM_152588.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.62
• Publications: 3 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
• hearing loss, autosomal recessive 122

  Inheritance: AR Classification: NO_KNOWN Submitted by: PanelApp Australia

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.092 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMTC2	NM_152588.3	MANE Select	c.2153-4053C>T		intron	N/A	NP_689801.1	Q8N394
	TMTC2	NM_001320321.2		c.1418-4053C>T		intron	N/A	NP_001307250.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMTC2	ENST00000321196.8	TSL:1 MANE Select	c.2153-4053C>T		intron	N/A	ENSP00000322300.3	Q8N394
	TMTC2	ENST00000549919.1	TSL:1	c.2135-4053C>T		intron	N/A	ENSP00000447609.1	A0A0B4J253
	TMTC2	ENST00000546590.2	TSL:1	n.*1474-4053C>T		intron	N/A	ENSP00000448630.2	F8VRQ2

Frequencies

GnomAD3 genomes AF: 0.0729 AC: 11090 AN: 152066 Hom.: 463 Cov.: 33

Gnomad AFR AF: 0.0940

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0553

Gnomad ASJ AF: 0.0541

Gnomad EAS AF: 0.0808

Gnomad SAS AF: 0.0495

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0607

Gnomad OTH AF: 0.0676

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

GnomAD4 genome AF: 0.0731 AC: 11118 AN: 152184 Hom.: 465 Cov.: 33 AF XY: 0.0736 AC XY: 5476 AN XY: 74400

African (AFR) AF: 0.0944 AC: 3921 AN: 41516

American (AMR) AF: 0.0552 AC: 843 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0541 AC: 188 AN: 3472

East Asian (EAS) AF: 0.0814 AC: 422 AN: 5184

South Asian (SAS) AF: 0.0495 AC: 239 AN: 4826

European-Finnish (FIN) AF: 0.113 AC: 1197 AN: 10576

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0608 AC: 4133 AN: 68028

Other (OTH) AF: 0.0664 AC: 140 AN: 2108

Alfa AF: 0.0633 Hom.: 575

Bravo AF: 0.0715

Asia WGS AF: 0.0720 AC: 249 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.51
DANN	Benign	0.71
PhyloP100		-1.6
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: rs7304787; hg19: chr12-83440630;