Genetic Variant NM_080751.3:c.555-8C>A (chr20-2572171-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. 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

Publications

0 publications found

Variant links:

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]

TMC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

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>A		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>A		splice_region intron	N/A	ENSP00000351732.1	Q8TDI7-1
	TMC2	ENST00000644205.1		n.714-8C>A		splice_region intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

117142

Hom.:

Cov.:

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.:

Cov.:

AF XY:

0.000142

AC XY:

AN XY:

675870

show subpopulations

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

African (AFR)

AF:

0.000798

AC:

AN:

26314

American (AMR)

AF:

0.00

AC:

AN:

35398

Ashkenazi Jewish (ASJ)

AF:

0.0000435

AC:

AN:

23004

East Asian (EAS)

AF:

0.0000268

AC:

AN:

37256

South Asian (SAS)

AF:

0.0000133

AC:

AN:

75072

European-Finnish (FIN)

AF:

0.000103

AC:

AN:

48448

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5252

European-Non Finnish (NFE)

AF:

0.000165

AC:

173

AN:

1051244

Other (OTH)

AF:

0.000161

AC:

AN:

55788

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.263

Heterozygous variant carriers

120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

117192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

57102

African (AFR)

AF:

0.00

AC:

AN:

23538

American (AMR)

AF:

0.00

AC:

AN:

13248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2990

East Asian (EAS)

AF:

0.00

AC:

AN:

4670

South Asian (SAS)

AF:

0.00

AC:

AN:

4222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7694

Middle Eastern (MID)

AF:

0.00

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

58018

Other (OTH)

AF:

0.00

AC:

AN:

1710

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

7.3

(source)

DANN

Benign

0.48

PhyloP100

0.89

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over