rs12317459

Variant names:

• chr12-82770777-G-A
• rs12317459
• NM_152588.3:c.83+83108G>A

Variant summary

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

The NM_152588.3(TMTC2):​c.83+83108G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.213 in 151,926 control chromosomes in the GnomAD database, including 3,824 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 0.21 (3824 hom., cov: 31)
• Consequence: TMTC2 NM_152588.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.04
• Publications: 11 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.304 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.83+83108G>A		intron	N/A	NP_689801.1	Q8N394
	TMTC2	NM_001320322.2		c.83+83108G>A		intron	N/A	NP_001307251.1	F8VSH2
	TMTC2	NM_001320321.2		c.-82+83108G>A		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.83+83108G>A		intron	N/A	ENSP00000322300.3	Q8N394
	TMTC2	ENST00000549919.1	TSL:1	c.65+9841G>A		intron	N/A	ENSP00000447609.1	A0A0B4J253
	TMTC2	ENST00000548305.5	TSL:1	c.83+83108G>A		intron	N/A	ENSP00000448292.1	F8VSH2

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32317 AN: 151808 Hom.: 3811 Cov.: 31

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.206

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

GnomAD4 genome AF: 0.213 AC: 32359 AN: 151926 Hom.: 3824 Cov.: 31 AF XY: 0.209 AC XY: 15533 AN XY: 74242

African (AFR) AF: 0.309 AC: 12784 AN: 41382

American (AMR) AF: 0.149 AC: 2266 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 894 AN: 3462

East Asian (EAS) AF: 0.0106 AC: 55 AN: 5172

South Asian (SAS) AF: 0.126 AC: 609 AN: 4818

European-Finnish (FIN) AF: 0.202 AC: 2132 AN: 10558

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.190 AC: 12904 AN: 67970

Other (OTH) AF: 0.204 AC: 430 AN: 2106

Alfa AF: 0.194 Hom.: 10593

Bravo AF: 0.213

Asia WGS AF: 0.0810 AC: 282 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.15
DANN	Benign	0.69
PhyloP100		-1.0
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: rs12317459; hg19: chr12-83164556;