chr20-2572171-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_080751.3(TMC2):​c.555-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00084 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMC2 NM_080751.3 splice_region, intron
• Scores: Splicing: ADA: 0.00004928
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.894
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 20-2572171-C-T is Benign according to our data. Variant chr20-2572171-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 769064.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080751.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC2	NM_080751.3	MANE Select	c.555-8C>T		splice_region intron	N/A	NP_542789.2	Q8TDI7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC2	ENST00000358864.2	TSL:1 MANE Select	c.555-8C>T		splice_region intron	N/A	ENSP00000351732.1	Q8TDI7-1
	TMC2	ENST00000644205.1		n.714-8C>T		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000581 AC: 68 AN: 116952 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000756

Gnomad ASJ AF: 0.000335

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00300

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000328

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00225 AC: 413 AN: 183698 AF XY: 0.00195

Gnomad AFR exome AF: 0.00776

Gnomad AMR exome AF: 0.000879

Gnomad ASJ exome AF: 0.00225

Gnomad EAS exome AF: 0.00122

Gnomad FIN exome AF: 0.00524

Gnomad NFE exome AF: 0.00165

Gnomad OTH exome AF: 0.00214

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000844 AC: 1145 AN: 1356554 Hom.: 1 Cov.: 32 AF XY: 0.000855 AC XY: 577 AN XY: 675146

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00380 AC: 100 AN: 26282

American (AMR) AF: 0.00435 AC: 153 AN: 35196

Ashkenazi Jewish (ASJ) AF: 0.00196 AC: 45 AN: 22942

East Asian (EAS) AF: 0.000242 AC: 9 AN: 37224

South Asian (SAS) AF: 0.00204 AC: 153 AN: 74820

European-Finnish (FIN) AF: 0.00540 AC: 259 AN: 47984

Middle Eastern (MID) AF: 0.00172 AC: 9 AN: 5244

European-Non Finnish (NFE) AF: 0.000355 AC: 373 AN: 1051114

Other (OTH) AF: 0.000789 AC: 44 AN: 55748

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000581 AC: 68 AN: 117000 Hom.: 0 Cov.: 29 AF XY: 0.000632 AC XY: 36 AN XY: 57002

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00102 AC: 24 AN: 23446

American (AMR) AF: 0.0000755 AC: 1 AN: 13246

Ashkenazi Jewish (ASJ) AF: 0.000335 AC: 1 AN: 2988

East Asian (EAS) AF: 0.00 AC: 0 AN: 4670

South Asian (SAS) AF: 0.00 AC: 0 AN: 4222

European-Finnish (FIN) AF: 0.00300 AC: 23 AN: 7656

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.000328 AC: 19 AN: 57966

Other (OTH) AF: 0.00 AC: 0 AN: 1704

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00319 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.2
DANN	Benign	0.43
PhyloP100		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000049
SpliceAI score (max)		0.060		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: rs757672864; hg19: chr20-2552817;