rs7961953

Variant names:

• chr12-82698057-G-A
• rs7961953
• NM_152588.3:c.83+10388G>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+10388G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 152,140 control chromosomes in the GnomAD database, including 2,117 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 0.16 (2117 hom., cov: 32)
• Consequence: TMTC2 NM_152588.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.513
• Publications: 20 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.346 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMTC2	NM_152588.3	c.83+10388G>A		intron_variant	Intron 1 of 11	ENST00000321196.8	NP_689801.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMTC2	ENST00000321196.8	c.83+10388G>A		intron_variant	Intron 1 of 11	1	NM_152588.3	ENSP00000322300.3
TMTC2	ENST00000548305.5	c.83+10388G>A		intron_variant	Intron 1 of 5	1		ENSP00000448292.1
TMTC2	ENST00000546590.2	n.83+10388G>A		intron_variant	Intron 1 of 10	1		ENSP00000448630.2
TMTC2	ENST00000551915.5	n.790+10388G>A		intron_variant	Intron 1 of 7	1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23815 AN: 152022 Hom.: 2112 Cov.: 32

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.0518

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.0918

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.177

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

GnomAD4 genome AF: 0.157 AC: 23837 AN: 152140 Hom.: 2117 Cov.: 32 AF XY: 0.158 AC XY: 11730 AN XY: 74374

African (AFR) AF: 0.167 AC: 6942 AN: 41504

American (AMR) AF: 0.209 AC: 3203 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 575 AN: 3472

East Asian (EAS) AF: 0.360 AC: 1859 AN: 5166

South Asian (SAS) AF: 0.224 AC: 1082 AN: 4822

European-Finnish (FIN) AF: 0.0918 AC: 973 AN: 10594

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.128 AC: 8729 AN: 67984

Other (OTH) AF: 0.179 AC: 377 AN: 2106

Alfa AF: 0.150 Hom.: 341

Bravo AF: 0.166

Asia WGS AF: 0.281 AC: 975 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.16
DANN	Benign	0.55
PhyloP100		-0.51
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: rs7961953; hg19: chr12-83091836; COSMIC: COSV107354271;