Genetic Variant TMC2:c.934-102G>A (chr20-2594723-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.26

Publications

1 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: Benign. The variant received -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	Effect	Exon rank	MANE	Protein	UniProt
TMC2	NM_080751.3 link	c.934-102G>A	intron_variant	Intron 8 of 19	ENST00000358864.2	NP_542789.2	Q8TDI7-1
TMC2	XM_005260660.5 link	c.1009-102G>A	intron_variant	Intron 6 of 17		XP_005260717.1
TMC2	XR_001754152.2 link	n.1143-102G>A	intron_variant	Intron 6 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC2	ENST00000358864.2 link	c.934-102G>A		intron_variant	Intron 8 of 19	1	NM_080751.3	ENSP00000351732.1		Q8TDI7-1
TMC2	ENST00000644205.1 link	n.1093-102G>A		intron_variant	Intron 6 of 14

Frequencies

GnomAD3 genomes

AF:

0.0250

AC:

3797

AN:

152066

Hom.:

154

Cov.:

show subpopulations

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.:

AF XY:

0.00262

AC XY:

1486

AN XY:

567434

show subpopulations

African (AFR)

AF:

0.0800

AC:

2087

AN:

26092

American (AMR)

AF:

0.00710

AC:

222

AN:

31262

Ashkenazi Jewish (ASJ)

AF:

0.00382

AC:

AN:

19114

East Asian (EAS)

AF:

0.0000267

AC:

AN:

37396

South Asian (SAS)

AF:

0.000213

AC:

AN:

65582

European-Finnish (FIN)

AF:

0.000102

AC:

AN:

49156

Middle Eastern (MID)

AF:

0.00656

AC:

AN:

4570

European-Non Finnish (NFE)

AF:

0.000601

AC:

513

AN:

853372

Other (OTH)

AF:

0.00700

AC:

340

AN:

48602

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

146

292

439

585

731

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<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

AF:

0.0250

AC:

3812

AN:

152184

Hom.:

155

Cov.:

AF XY:

0.0246

AC XY:

1833

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.0845

AC:

3508

AN:

41498

American (AMR)

AF:

0.0132

AC:

202

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68008

Other (OTH)

AF:

0.0185

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

169

338

507

676

845

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0274

Hom.:

Bravo

AF:

0.0290

Asia WGS

AF:

0.00462

AC:

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

(source)

DANN

Benign

0.53

PhyloP100

-1.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over