chr20-2572171-C-A

Variant names:

• chr20-2572171-C-A
• rs757672864
• NM_080751.3:c.555-8C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_080751.3(TMC2):​c.555-8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000155 in 1,357,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMC2 NM_080751.3 splice_region, intron
• Scores: Splicing: ADA: 0.02166
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.894

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC2	NM_080751.3	c.555-8C>A		splice_region_variant, intron_variant	Intron 4 of 19	ENST00000358864.2	NP_542789.2
TMC2	XM_005260660.5	c.630-8C>A		splice_region_variant, intron_variant	Intron 2 of 17		XP_005260717.1
TMC2	XR_001754152.2	n.764-8C>A		splice_region_variant, intron_variant	Intron 2 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC2	ENST00000358864.2	c.555-8C>A		splice_region_variant, intron_variant	Intron 4 of 19	1	NM_080751.3	ENSP00000351732.1
TMC2	ENST00000644205.1	n.714-8C>A		splice_region_variant, intron_variant	Intron 2 of 14

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 117142 Hom.: 0 Cov.: 29 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000155 AC: 211 AN: 1357776 Hom.: 0 Cov.: 32 AF XY: 0.000142 AC XY: 96 AN XY: 675870

Gnomad4 AFR exome AF: 0.000798

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000435

Gnomad4 EAS exome AF: 0.0000268

Gnomad4 SAS exome AF: 0.0000133

Gnomad4 FIN exome AF: 0.000103

Gnomad4 NFE exome AF: 0.000165

Gnomad4 OTH exome AF: 0.000161

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 117192 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 57102

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.3
DANN	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.022
SpliceAI score (max)		0.11		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: rs757672864; hg19: chr20-2552817;