rs10485601

Positions:

• chr20-2613544-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000358864.2(TMC2):​c.1872+222C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 551,424 control chromosomes in the GnomAD database, including 7,061 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 0.14 (1650 hom., cov: 32)
  • Exomes 𝑓: 0.16 (5411 hom.)
• Consequence: TMC2 ENST00000358864.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.29

Genes affected

TMC2 (HGNC:16527): (transmembrane channel like 2) This gene encodes a transmembrane protein that is necesssary for mechanotransduction in cochlear hair cells of the inner ear. Mutations in this gene may underlie hereditary disorders of balance and hearing. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC2	NM_080751.3	c.1872+222C>T		intron_variant		ENST00000358864.2	NP_542789.2
TMC2	XM_005260660.5	c.1947+222C>T		intron_variant			XP_005260717.1
TMC2	XR_001754152.2	n.2303C>T		non_coding_transcript_exon_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC2	ENST00000358864.2	c.1872+222C>T		intron_variant		1	NM_080751.3	ENSP00000351732	P1
TMC2	ENST00000496948.2	c.*96C>T		3_prime_UTR_variant, NMD_transcript_variant	4/6	2		ENSP00000495303
TMC2	ENST00000644205.1	n.1936-289C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20604 AN: 152012 Hom.: 1652 Cov.: 32

Gnomad AFR AF: 0.0664

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.158

GnomAD4 exome AF: 0.157 AC: 62635 AN: 399294 Hom.: 5411 Cov.: 6 AF XY: 0.155 AC XY: 33286 AN XY: 214288

Gnomad4 AFR exome AF: 0.0669

Gnomad4 AMR exome AF: 0.138

Gnomad4 ASJ exome AF: 0.222

Gnomad4 EAS exome AF: 0.0109

Gnomad4 SAS exome AF: 0.125

Gnomad4 FIN exome AF: 0.156

Gnomad4 NFE exome AF: 0.176

Gnomad4 OTH exome AF: 0.165

GnomAD4 genome AF: 0.135 AC: 20599 AN: 152130 Hom.: 1650 Cov.: 32 AF XY: 0.133 AC XY: 9857 AN XY: 74348

Gnomad4 AFR AF: 0.0665

Gnomad4 AMR AF: 0.143

Gnomad4 ASJ AF: 0.227

Gnomad4 EAS AF: 0.0106

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.155

Gnomad4 NFE AF: 0.177

Gnomad4 OTH AF: 0.156

Alfa AF: 0.164 Hom.: 1257

Bravo AF: 0.133

Asia WGS AF: 0.0640 AC: 225 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.4
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10485601; hg19: chr20-2594190;