NM_152588.3:c.301C>T

Variant names:

• chr12-82857227-C-T
• rs758121782
• NM_152588.3:c.301C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152588.3(TMTC2):​c.301C>T​(p.Leu101Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMTC2 NM_152588.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.35
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.301C>T	p.Leu101Phe	missense	Exon 2 of 12	NP_689801.1	Q8N394
	TMTC2	NM_001320322.2		c.301C>T	p.Leu101Phe	missense	Exon 2 of 6	NP_001307251.1	F8VSH2
	TMTC2	NM_001320321.2		c.-81-38591C>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.301C>T	p.Leu101Phe	missense	Exon 2 of 12	ENSP00000322300.3	Q8N394
	TMTC2	ENST00000549919.1	TSL:1	c.283C>T	p.Leu95Phe	missense	Exon 3 of 13	ENSP00000447609.1	A0A0B4J253
	TMTC2	ENST00000548305.5	TSL:1	c.301C>T	p.Leu101Phe	missense	Exon 2 of 6	ENSP00000448292.1	F8VSH2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.0087	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.081	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		3.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.015	D
Polyphen		0.97	D
Vest4		0.35
MutPred		0.61		Loss of stability (P = 0.1089)
MVP		0.52
MPC		0.65
ClinPred		0.94	D
GERP RS		3.8
Varity_R		0.31
gMVP		0.81
Mutation Taster		=47/53	disease causing

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: rs758121782; hg19: chr12-83251006; COSMIC: COSV58278824;