rs6115181

Positions:

• chr20-2613608-A-G

Variant summary

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

The NM_080751.3(TMC2):​c.1872+286A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 381,876 control chromosomes in the GnomAD database, including 11,899 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 0.24 (4344 hom., cov: 32)
  • Exomes 𝑓: 0.25 (7555 hom.)
• Consequence: TMC2 NM_080751.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.472

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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC2	NM_080751.3	c.1872+286A>G		intron_variant		ENST00000358864.2	NP_542789.2
TMC2	XM_005260660.5	c.1947+286A>G		intron_variant			XP_005260717.1
TMC2	XR_001754152.2	n.2367A>G		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+286A>G		intron_variant		1	NM_080751.3	ENSP00000351732	P1
TMC2	ENST00000496948.2	c.*160A>G		3_prime_UTR_variant, NMD_transcript_variant	4/6	2		ENSP00000495303
TMC2	ENST00000644205.1	n.1936-225A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35884 AN: 151932 Hom.: 4345 Cov.: 32

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.268

GnomAD4 exome AF: 0.250 AC: 57515 AN: 229826 Hom.: 7555 Cov.: 3 AF XY: 0.254 AC XY: 31775 AN XY: 125256

Gnomad4 AFR exome AF: 0.223

Gnomad4 AMR exome AF: 0.299

Gnomad4 ASJ exome AF: 0.263

Gnomad4 EAS exome AF: 0.311

Gnomad4 SAS exome AF: 0.290

Gnomad4 FIN exome AF: 0.242

Gnomad4 NFE exome AF: 0.229

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.236 AC: 35905 AN: 152050 Hom.: 4344 Cov.: 32 AF XY: 0.237 AC XY: 17619 AN XY: 74312

Gnomad4 AFR AF: 0.213

Gnomad4 AMR AF: 0.251

Gnomad4 ASJ AF: 0.263

Gnomad4 EAS AF: 0.305

Gnomad4 SAS AF: 0.295

Gnomad4 FIN AF: 0.249

Gnomad4 NFE AF: 0.233

Gnomad4 OTH AF: 0.266

Alfa AF: 0.239 Hom.: 6076

Bravo AF: 0.240

Asia WGS AF: 0.299 AC: 1039 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.5
DANN	Benign	0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs6115181; hg19: chr20-2594254;