rs6050469

Positions:

• chr20-2594723-G-A

Variant summary

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

The NM_080751.3(TMC2):​c.934-102G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00551 in 1,287,330 control chromosomes in the GnomAD database, including 247 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 0.025 (155 hom., cov: 31)
  • Exomes 𝑓: 0.0029 (92 hom.)
• Consequence: TMC2 NM_080751.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26

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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC2	NM_080751.3	c.934-102G>A		intron_variant		ENST00000358864.2	NP_542789.2
TMC2	XM_005260660.5	c.1009-102G>A		intron_variant			XP_005260717.1
TMC2	XR_001754152.2	n.1143-102G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC2	ENST00000358864.2	c.934-102G>A		intron_variant		1	NM_080751.3	ENSP00000351732	P1
TMC2	ENST00000644205.1	n.1093-102G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3797 AN: 152066 Hom.: 154 Cov.: 31

Gnomad AFR AF: 0.0844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0187

GnomAD4 exome AF: 0.00289 AC: 3285 AN: 1135146 Hom.: 92 AF XY: 0.00262 AC XY: 1486 AN XY: 567434

Gnomad4 AFR exome AF: 0.0800

Gnomad4 AMR exome AF: 0.00710

Gnomad4 ASJ exome AF: 0.00382

Gnomad4 EAS exome AF: 0.0000267

Gnomad4 SAS exome AF: 0.000213

Gnomad4 FIN exome AF: 0.000102

Gnomad4 NFE exome AF: 0.000601

Gnomad4 OTH exome AF: 0.00700

GnomAD4 genome AF: 0.0250 AC: 3812 AN: 152184 Hom.: 155 Cov.: 31 AF XY: 0.0246 AC XY: 1833 AN XY: 74408

Gnomad4 AFR AF: 0.0845

Gnomad4 AMR AF: 0.0132

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.0126 Hom.: 13

Bravo AF: 0.0290

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.2
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs6050469; hg19: chr20-2575369;